MX2007015173A - Tricyclic 6-alkylidene-penems as class-d beta-lactamases inhibitors. - Google Patents

Abstract

This invention relates to certain tricyclic 6-alkylidene penems which act as a inhibitor of class-D enzymes. ????-Lactamases hydrolyze ????-lactam antibiotics, and as such serve as the primary cause of bacterial resistance. The compounds of the present invention when combined with ????-lactam antibiotics will provide an effective treatment against life threatening bacterial infections. In accordance with the present invention there are provided compounds of formula I which are useful for treatment of bacterial infections having class-D enzymes associated therewith (Formula I): wherein: One of A and B denotes hydrogen and the other an optionally substituted fused tricyclic heteroaryl group; and X is S or O.

Description

6-ALKYLIDENIC TRICYCLIC PENEMIS AS CLASS D ß-LACTAMASE INHIBITORS This invention relates to certain tricyclic 6-alkylidene penises which act as inhibitors of the class D enzymes. The β-lactamases hydrolyse the β-lactam antibiotics, and as such serve as the primary cause of bacterial resistance. The compounds of the present invention when combined with the β-lactam antibiotics will provide an effective treatment against lethal bacterial infections.

BACKGROUND OF THE INVENTION Class D β-lactamases are the smallest (27 kDa) among the active site serine β-lactamases. These enzymes lack the total amino acid sequence (lower 20% amino acid identity) with the more prevalent and better understood β-lactamases of classes A and C (Naas, T. And Nordmann, P. Curr. Pharm. 1999, 5,865-879). To date, almost 30 classes of D enzymes are known. Class D β-lactamases are also called oxacillinases because of their ability to hydrolyse oxacillin and cloxacillin two to four times faster than classical penicillins such as penicillin G (Ledent). , P., Raquel, X, Joris, B. VanBeemen, J, Frere, JM Biochem J. 1993,292,555-562). They are designated by OXA-1, OXA-2, etc., and fall into at least five subgroups on the basis of phylogenetic analysis (Barlow, M, Hall, B.G., J. Mol, Evol. 2002, 55, 314-321.). OXA-1 is the most common of class D enzymes and is found in up to 10% of Escherichia coli isolates, in Pseudomonas aeruginosa in epidemic strains of salmonellae (Medeiros, AA Brit. Med. J. 1984, 40,18 -27). Genes for most of these enzymes are carried as chromosome-mediated or plasmid-mediated, which facilitates their spread among various organisms. The usual knowledge about the catalytic mechanism of β-lactamases class D is very limited (Golemi, D, Maveyraud, L, Vakulenko, S, Trainer, S, Ishiwata, A, Kotra, LP, Samana, JP., Mobashery, SJ Am. Chem. Soc. 2000, 122.6132-6133). Class D enzymes are dimeric, however, OXA-1 Escherichia coli is found to be monomeric and in solution and in crystal, (Sun, T, Nukuga, M, Mayana, K, Braswell, EH, Knox, JR Protein Sci., 2003, 12.82-91). As a result of point mutations and plasmid transfer, natural OXA variants (ie OXA-15, OXA-18, OXA-19) have emerged with an expanded substrate spectrum including imipenem and third generation cephalosporins such as cefotaxin , ceftriazone, and aztreonam although new variants such as OXA-11 and OXA-14 to OXA-20 show an extended spectrum profile (ESBL). These aspects make them clinically important (Buynak, J, Curr. Med. Chem., 2004, 11, 1951-1964).

Penicillins, cephalosporins and carbapenems are the most frequent ß-lactam antibiotics widely used in the clinical area. However, the development of resistance to ß-lactam antibiotics by different pathogens has had a harmful effect on the maintenance of the effective treatment of bacterial infections (Coleman, K. Expert Opin, Invest. Drugs 1995, 4, 693; Sutherland, R. Infection HS95, 23, 191; Bush, K, Cur. Pharm. Desing 1999, 5, 839-845). The most significantly known mechanism related to the development of bacterial resistance to β-lactam antibiotics is the production of β-lactamases class A, class B, class C, and class D. These enzymes degrade β-lactam antibiotics, give as a result the loss of antibacterial activity. Class A enzymes preferably hydrolyse penicillins, classes B hydrolyse all ß-lactams including carbapenems, class C ß-lactamases have a substrate profile that favors the hydrolysis of the cephalosporin, while the substrate preference for β-lacfamases class B include oxacillin (Bush, K., Jacoby, GA, Medeiros, AA Antimicrob, Agents Chemother, 1995, 39, 1211). To date more than 250 different ß-lactamases have been reported (Payne, D. J,: Du, W and Bateson, JH Exp. Opin, Invest. Drugs 2000, 247.) and the need for a new generation of inhibitors remains of broad spectrum ß-lactamase. Bacterial resistance to these antibiotics could be greatly reduced by administering the ß-lactam antibiotic in combination with a compound that inhibits these enzymes.

Commercially available β-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are all effective against the pathogens that produce class A. Clavulanic acid is clinically used in combination with amoxicillin and ticarcillin; similarly, sulbactam with ampicillin and tazobactam with piperacillin. However, these compounds are ineffective against organisms that produce class C. The mechanism of inactivation of β-lactamases class A (such as PCI and TEM-1) has been elucidated. (Bush, K., Antimicrob, Agents Chemother, 11393, 37, 851, Yang, Y .; Janota, K .; Tabei, K .; Huang, N .; Seigal, MM; Lin, YI; Rasmussen, BA and Shiaes. , DMJ Biol. Chem. 2000, 35, 26674). To date, no inhibitors of class D enzymes have been reported in clinical use.

Recently, a number of 6-methylidene penises carrying a bicyclic heterocycle have been described as the class A, class B and class C beta-lactamase inhibitors.

(WO2003093280). In addition a number of 6-methylidene penmes bearing a tricyclic heterocycle such as β-lactamase inhibitors, class A, class B and class C have been described in US 2004-00043978A1 which is incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel low molecular weight and broad spectrum β-lactam compounds and in particular to a class of 6-alkylidene substituted with tricyclic heteroaryl having β-lactamase inhibitory activity class D when used in combination with ß-lactam antibiotics improve the antibacterial properties of the antibiotic. The compounds are therefore useful in the treatment of antibacterial infections in humans or animals either alone or in combination with other antibiotics. The compounds of the invention can be prepared by the procedures described in US 2004-00043978A1 which is incorporated herein by reference.

According to the present invention, compounds of the formula 1 which are useful for the treatment of bacterial infections having class D enzymes associated with these are provided: where: One of A and B denotes hydrogen and the other an optionally substituted fused tricyclic heteroaryl group; X is S or O, preferably S; R5 is H, an in vivo hydrolysable ester such as C1-C6 alkyl, C5-C6 cycloalkyl, CHR3OCOC1-C6 or salts such as Na, K, Ca; the preferred R5 groups are H or the salts.

The term "fused tricyclic heteroaryl group" is used in the specification and claims to mean: a group comprising three fused rings in which at least one ring has an aromatic character (ie it complies with the Huckel rule (4n + 2)). The fused tricyclic heteroaryl group contains 1-6 heteroatoms selected from the group consisting of O, S, N and NR The fused tricyclic heteroaryl must be attached through a carbon preferably in one of at least one of the aromatic rings to the remainder of the the molecule of formula 1. The fused tricyclic heteroaryl group may contain 1-3 aromatic rings and 0-2 non-aromatic rings. Each of the aromatic rings in the fused tricyclic heteroaryl group may contain 5 to 7 ring atoms (including bridgehead atoms) selected from CR2, O, S, N, and NR Each of the aromatic ring (s) of the heterocyclic heterocyclic group may contain 0 to 3 heteroatoms selected from O, S, N, and NR The nonaromatic ring (s), if any, of the fused tricyclic heteroaryl group may contain 5-8 ring atoms (including the head atoms) bridge) and contain 0-4 heteroatoms selected from N N-Rt O or S (O) n, where n is 0-2. In each non-aromatic ring of the fused tricyclic heteroaryl group, one or two of the non-bridgehead carbon atoms may each be optionally substituted with one or two R4I each R4 may independently be the same or different. Examples of fused tricyclic heteroaryl are optionally substituted ring systems such as midazo [2,1-b] [1,3] benzothiazole optionally substituted for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo (such as chloro or fluorine); Imidazo [1,2-a] quinoline; 6,7-dihydro-5H-cyclopenta [d] imidazole [2,1-b] [1,3] thiazole; imidazole [1,2-a] quinoxaline; 5,6,7,8-tetrahydro- [1, 2,4] triazolo [1, 5-a] pyridine dibenzo [b, f] [1,4] -oxazepin-11 (10H) -one optionally substituted eg , by aryalkyl such as benzyl 7,8-dihydro-6H-3,4,8b-triaza-as-indacene optionally substituted by C 1 -C 6 alkoxy; 4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepine, optionally substituted, for example, by C 1 -C 6 alkoxy; 5H-imidazo [2,1-a] isoindol; 5,8-d: hydro-6H-imidazo [2,1-b] pyrano [4,3-d] [1,3] thiazole; imidazo [2,1-b] benzothiazole; [1,3] thiazolone [3,2-ajbenzimidazole; 7,8-dihydro-6H-cyclopenta [3,4] pyrazolo [5,1-b3 [1,3] thiazole; 5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] -benzothiazole; 9H-imidazo [1, 2-a] benzimidazole optionally substituted eg by C1-C6 alkyl; 4H-thieno [2 ', 3': 4,5] thiopyrano [2,3-b] pyridine; 7,8-dihydro-6H-cyclopenta [e] [1, 2,4] -triazolo [1,5-a] pyrimidine optionally substituted eg by C 1 -C 6 alkyl; 6,7,8,9-tetrahydropyrido [3,4-e] [1,2,4] triazolo [1,5-a] pyrimidine optionally substituted eg by C 2 -C 7 alkoxycarbonyl; 8 ', 9'-dihydro-6'H-spiro [1,3-dioxolan-2,7' - [1, 2,4] triazolo [1, 5-a] -quinazoline; 6,7,8,9-tetrahydro [1,2,4] triazolo [1,5-a] quinazoline optionally substituted eg by C 1 -C 6 alkyl; 7,8-dihydro-6H-cyclopenta [e] imidazo [1,2-a] pyrimidine optionally substituted, for example, by C 1 -C 6 alkoxy; 7,8-dihydro-6H-cyclopenta [e] imidazo [1,2-a] pyrimidinyl optionally substituted, for example, by arylalkyloxyalkylaxy; 3-dihydro [1,3] thiazolo [3,2-a] -benzimidazole; 2,3-dihydro [1,3] thiazolo [3,2-a] benzimidazole; 4-dihydro-2H- [1, 3] thiazino [3,2-a] -benzimidazole; [1, 3] thiazolo [3,2-a] benzimidazole; 7,8-dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazole; 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] benzoxazole; and 5,6,7,8-tetrahydropyrazolo [5 ', 1': 2,3] [1,3] oxazolo [5,4-c] pyridine optionally substituted, for example, by C 2 -C 7 alkoxycarbonyl.

Ri is H, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or saturated mono or bicyclic heterocycles, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 6 alkenyl, C 3 -C 6 alkynyl optionally substituted with the proviso that both , the double bond and triple bond must not be present in the carbon atom that is directly bound to N; per fluoro optionally substituted C 1 -C 6 alkyl, alkyl or aryl optionally substituted by -S (O) p wherein p is 2, -C = O optionally substituted heteroaryl, -C = optionally substituted aryl, -C = O alkyl (C 1 - C6), optionally substituted, -C = O (C3-C6) cycloalkyl optionally substituted, -C = O optionally substituted mono or bicyclic saturated heterocyclics, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkylheteroaryl, aryl-C1-6alkyl Optionally substituted C6, optionally substituted heteroaryl-C1-C6-alkyl, saturated monos or bicyclics optionally substituted C1-C6alkyl, optionally substituted arylalkenyl of 8 to 16 carbon atoms, -CONR6R7, -SO2NR6R7, optionally substituted arylalkyloxyalkyl, -alkyl-O -acyl-eryl, optionally substituted, -alkyl-O-alkyl-heteroaryl optionally substituted, aryloxyalkyl optionally substituted, heteroaryloxyalkyl optionally substituted, aryloxyaryl optional substituted, optionally substituted aryloxyheteroaryl, aryloxyaryl optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl aryloxyheteroaryl, optionally substituted alkyl aryloxy alkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted healkoxyloxycarbonyl. Preferred R groups are H, optionally substituted alkyl, optionally substituted aryl, -C = (C1-C6) alkyl, C3-C6 alkenyl, C3-C6 alkynyl, optionally substituted cycloalkyl, SO2alkyl, SO2aryl, optionally substituted heterocycles, -CONR6R7, and optionally substituted heteroaryl.

R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl having 1 to 2 double bonds, C2-C6 alkynyl, optionally substituted having 1 to 2 triple bonds, halogen, cyano, N-RßR7, C1 alkoxy C6 optionally substituted, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR6, optionally substituted alkyl aryloxy alkylamine, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6alkoxy, alkylenedioxy, optionally substituted aryloxy-C1-C6 alkylamine, C1-C6 perfluoroalkyl, C1-C6 alkyl optionally substituted by S (O) q-, aryl optionally substituted by, S (O) q. where q is 0, 1 or 2, CONRßR7, guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6alkyl, saturated mono or bicyclic monocyclic alkyl or C1-C6 heteroaryl C6 optionally substituted, arylalkenyl of optionally substituted 8 to 16 carbon atoms, SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted heteroeryloxyaryl, aryloxyaryl optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkylaryloxyalkylamines, optionally substituted C3-C7 cycloalkyl, saturated heterocyclic or partially saturated C3-C7 optionally substituted. Preferred R2 groups are H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroaryl, halogen, CN, hydroxy, optionally substituted heterocycle, -CONR6R7, COORß, optionally substituted aryl, S (O) q-alkyl, and S (O ) q-aryl.

R3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Preferred R3 groups are H or C1-C6 alkyl.

R4 is H, optionally substituted C1-C6 alkyl, one of R4 is OH, C1-C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7; or R4R can be together = O or R4R together with the carbon atom to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S = (O) n ( where n = 0 to 2), NR ^ the preferred R4 groups are H, C1-C6 alkyl, NR6R7, or R R4 together with the carbon to which they are attached form a spiro system of five to eight members.

R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, R6 and R7 can together with the nitrogen to which they are adhered they form a saturated ring system of 3 to 7 members which optionally has one or two heteroatoms such as N-R1 t O, S = (O) nn = 0-2. Preferred groups Re and R7 are H, C1-C6 alkyl, arylalkyl, heteroarylalkyl, or R6 and R7 together with the nitrogen to which they are attached form a saturated 3 to 7 membered ring system.

Chemical Definitions The term "alkyl" means straight and branched chain alkyl portions of 1-12 carbons, preferably 1-6 carbon atoms.

The term "alkenyl" means straight and branched alkenyl portions of 2-8 carbon atoms containing at least one double bond, and no triple bond, preferably the alkenyl portion having 1 or two double bonds. Such alkenyl portions may exist in the E or Z conformations; The compounds of this invention include both conformations. In the case of alkenyl, heteroatoms such as O, S or N-R! they must not be present in the carbon that is bound to a double bond; The term "alkynyl" includes straight and branched chain alkynyl portions containing 2-6 carbon atoms containing at least one triple bond, preferably the alkynyl portion having one or two triple bonds. In the case of alkynyl, heteroatoms such as O, S or N-Rt should not be present in the carbon that is bonded to a double or triple bond; The term "cycloalkyl" refers to an alicyclic hydrocarbon group having 3-7 carbon atoms.

The term perfluoroalkyl is used herein to refer to straight and branched chain saturated aliphatic hydrocarbon groups having at least one carbon atom and two or more fluorine atoms. Examples include CF3, CH2CF3, CF2CF3 and CH (CF3) 2.

The term halogen is defined as Cl, Br, F and I.

If the alkyl, alkenyl, alkynyl, or cycloalkyl is "optionally substituted", one or two of the following are the possible substituents: nitro, -aryl. -heteroaryl, alkoxycarbonyl-. -alkoxy, -alkoxy-alkyl, -O-C2-C4alkyl-O-, -cyano, -halogen, -hydroxy, -N-R6R7I- COOH, -COO-alkyl, -trifluoromethyl, -trifluoromethoxy, arylalkyl, alkylaryl , R6R7N-alkyl-, HO-C1-C6alkyl-, alkoxyalkyl-, alkyl-S-, -SO2N-R- R7, -SO2NHR6, -CO2H, CONR6R7, aryl-O-, heteroaryl-O-, -S (O ) s-aryl (where s = 0-2), -alkyl-O-alkyl-NRßR7, -alkyl-aryl-O-alkylN-R6R7, C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-alkyl-O- R6R7N-alkyl alkyl-, and -S (O) s-heteroaryl (where S = 0-2); Preferred substituents for alkyl, alkenyl, alkynyl, and cycloalkyl include: halogen, nitro, aryl, heteroaryl, alkoxycarbonyl-, alkoxy, alkoxy-alkyl, -cyano, hydroxy, and -N-R6R7.

Aryl is defined as a portion of aromatic hydrocarbon selected from the group: phenyl group, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluoroenyl, indanyl, biphenylenyl, and acenaphtenyl. Preferred aryl groups are phenyl and biphenyl.

Heteroaryl is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) wherein the heteroaryl moieties are selected from: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imitiazole, N-methylimidazole, pyridine , pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1, 2,4-triazole, 1H-tetrazole, 1 -methyltetranol, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline; (2) a bicyclic aromatic heterocycle wherein a phenyl, pyridine, pyrimidine or pyridine ring is: (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having a nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having a nitrogen atom together with an oxygen atom or a sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having a heteroatom selected from O, N or S. Preferred heteroaryl groups are furan, oxazole, thiazole, isoxazole, siathiazole, imidazole, N-methylimidazole , pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1, 2,4-triazole, 1H-tetrazole , 1-methyltetrazole, quinoline, isoquinoline, and naphthyridine.

If the aryl or heteroaryl is "optionally substituted", one or two of the following are the possible substituents: nitro, -aryl, -heteroaryl, alkoxycarbonyl-, -alkoxy, -alkoxy-alkyl, alkyl-O-C2-C4alkyl- O-, -cyano, -halogen, -hydroxy, -N-R6R7, -trifluoromethyl, -trifluoromethoxy, arylalkyl, alkylaryl, R6R7N-alkyl-, HO-alkyl-C1-C6-, alkoxyalkyl-, alkyl-S-, - SO2N-R6R7, -SO2NHR6, -CO2H, CONR6R7, aryl-O-, heteroaryl-O-, -S (O) s-aryl (where s = 0-2), -alkyl-O-alkyl-O-NR6R7 -, -alkyl-aryl-O-alkylN-R6R7, C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-alkyl-O-R6R-N-alkyl- and -S (O) s-heteroaryl (wherein = 0-2); Preferred substituents for aryl and heteroaryl include: alkyl, halogen, -N-R6R7, trifluromethyl, -trifluoromethoxy, arylalkyl and alkylaryl.

Arylalkyl is defined as Aryl-C 1 -C 6 alkyl-; the arialkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents on the alkyl or aryl moiety as defined above.

Alkylaryl is defined as C 1 -C 6 -alkyl The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents on the aryl or alkyl moiety as defined above.

Heteroaryl-C 1 -C 6 -alkyl is defined as an alkyl portion substituted by heteroaryl wherein the alkyl chain is 1-6 carbon atoms (straight or branched). The alkyl heteroaryl moieties include heteroaryl- (CH2) 1-6- and the like. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents on the alkyl or heteroaryl moiety as defined above; C1-C6 alkyl heteroaryl is defining an alkyl chain of 1-6 carbon atoms (straight or branched) attached to a hereroaryl moiety, which is attached to the rest of the molecule. For example -alkyl-C1-C6-heteroaryl-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents on the alkyl or heteroaryl moiety as defined above; Saturated or partially saturated heterocycles are defined as heterocyclic rings selected from the is moiety; aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofurinyl, dihydrobenzothienyl, dihydrobenzoxazolyl, Dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihidropirrazinilo, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihidrofienilo, dihydrotriazolyl, dihydroazetidinyl, dihydro-1,4-dioxanyl, tetrahydrofuranyl, fefrahidrotienilo , tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Preferred saturated or partially saturated hephecyclics include: aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidino, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinylino, dihydroimidazole, and dihydroisooxazolyl.

Saturated or partially saturated mono or bicyclic C1-C6 alkyl heterocycles are defined as an alkyl group (straight or branched) of C1-C6 attached to heterocycles (defined above) through a carbon atom or a nitrogen atom and the other end of the alkyl chain adhered to the rest of the molecule. The term "optionally substituted" refers to unsubstituted or substituted with one or two substituents present on the alkyl or heterocyclic portion of the molecule, as defined above; Arylalkyloxyalkyl is defined as aryl C1-C6 alkyl-O-C1-C6 alkyl-. The term "optionally substituted" refers to unsubstituted or substituted with one or two substituents present in the alkyl and / or aryl portions as defined above; Alkylalkyl is defined as C1-C6 alkyl-O-C1-C6 alkyl-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl portion as defined above; Aryloxyalkyl is defined as aryl-O-C1-C6 alkyl-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl or aryl moiety as defined above; Heteroarylalkyloxyalkyl is defined as heteroarylC1-C6alkyl-O-C1-C6alkyl-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl or heteroaryl moiety as defined above; Aryloxyaryl is defined as aryl-O-aryl. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the aryl moiety as defined above; Aryloxyheteroaryl is defined as aryl-O-heteroaryl- or -aryl-O-heteroaryl; in this definition the aryl portion or the heteroaryl portion can adhere to the remaining portion of the molecule; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the aryl moiety or on the heteroaryl moiety as defined above; Alkylaryloxyaryl is defined as aryl-O-aryl-C 1 -C 6 -alkyl. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the aryl moiety as defined above; Alkylaryloxyheteroaryl is defined as heteroaryl-O-aryl-C1-C6alkyl-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the aryl moiety or on the heteroaryl moiety as defined above; Alkylaryloxyalkylamine is defined as R6R7N-C 1 -C 7 alkyl-aryl-alky [oC 1 -C 6 -. The terms "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the alkyl or aryl moiety as defined above; Re and R7 as defined above; Alkoxycarbonyl is defined as -alkyl-C1-C6-O-C = O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl portion of the alkoxy moiety as defined above; Aryloxycarbonyl is defined as aryl-O-C = O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the aryl moiety as defined above; Heteroarilloxycarbonyl is defined as heteroaryl-O-C = O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl or heteroaryl moiety as defined above; Alkoxy is defined as -alkyl-C1-C6-O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl portion as defined above; Aryloxy is defined as aryl-O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the aryl moiety as defined above; Heteroaryloxy is defined as heteroaryl-O-. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the heteroaryl portion as defined above; Alkenyloxy is defined as C3-C6 alkene-O-; Example allyl-O-, but-2-ene-O-, or similar portions. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkene portion as defined above, with the proviso that no heteroatom such as O, S, N-Ri is present in the carbon atom , which is attached to a double bond; Alkynyloxy is defined as C3-C6 alkyn-O-; Example CH triple bond C-CH2-O-, or similar portions. The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyne portion as defined above, with the proviso that no heteroatom such as O, S, or -R ^ is present on the carbon, which is attached to a double or triple bond; Alkylaminoalkoxy is defined as R6R7N-C1-C6-alkyl-O-C1-C6-alkyl, wherein the terminal alkyl group attached to oxygen is connected to the rest of the molecule; The terms R6 and R are defined above; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl portion as defined above; Alkylene dioxy is defined as -O-CH2-O or -O- (CH2) -O-; Aryloxyalkylamine is defined as R6R7N-C1-C6-alkyl-O-aryl-, wherein the aryl is attached to the rest of the molecule; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl or aryl moiety as defined above; Arylalkenyl is defined as aryl-alkeno-C2-C8, with the proviso that no heteroatom such as O, S, or N-Rt is present in the carbon atom that is adhered to a double bond; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the alkyl portion as defined above; Heteroaryloxyalkyl is defined as Heteroaryl-O-C1-C6alkyl-; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present on the heteroaryl portion as defined above; Heteroarylaryl is defined as Heteroaryl-O-aryl-, where the eryl portion is attached to the rest of the molecule; The term "optionally substituted" refers to unsubstituted or substituted with 1 or 2 substituents present in the heteroaryl portion or the aryl portion as defined above; Alkoxy, alkoxyalkyl, and alkylphyoalkyloxy are the portions wherein the alkyl chain is 1-6 carbon atoms (straight or branched). Aryloxy, heteroaryloxy, arylthio and heteroarylthio are the portions wherein the aryl and heteroaryl groups are as defined above. Arylalkyloxy, heteroarylalkyloxy, arylalkylthio and heteroarylalkylthio are the portions wherein the aryl and heteroaryl groups are as defined above and wherein the alkyl chain is 1-6 carbons (straight or branched). Aryloxyalkyl, heteroaryloxyalkyl, aryloxyalkyloxy and heteroaryloxyalkyloxy are substituents wherein the alkyl radical is 1-6 carbon atoms. The terms "monoalkylamino" and "dialkylamino" refer to the portions with one or two alkyl groups wherein the alkyl chain is 1-6 carbons and the groups may be the same or different. The terms "monoalkylaminoalkyl" and "dialkylaminoalkyl" refer to the monoalkylamino and dialkylamino portions with one or two alkyl groups (the same or different) attached to the nitrogen atom that is bonded to an alkyl group of 1 to 3 carbon atoms.

The pharmaceutically acceptable salts are those salts that can be administered or delivered to a warm-blooded animal, preferably sodium, potassium or calcium or alkaline earth metal salts.

Preferably the compound of formula I has the following stereochemistry: Examples of the tricyclic heteroaryl group A and B: The arrangements and size of the ring (5-5-5). 1-8 In both formulas 1-A and -BZ, Z2, Z3, Z4, Z5, Zß, and Z7, they are independently selected from CR2, N, O, S or N-Ri and as mentioned above one of Z Z7 it is a carbon atom to which the rest of the molecule is attached. Y1t Y2, Y3 and Y can independently be C or N.

The layout and size of the ring: (5-5-6).

In both formulas 2-A v 2-B ZL Z2, Z3, Z4, Z5, Zß, Z7, and Z8 are independently selected from CR2, N, O, S or HR and as mentioned above one of the Z Z8 is a carbon atom to which the rest of the molecule is attached. Yi, Y, Y3 and Y4 can independently be C or N.

The layout and size of the ring (5-6-5). 3-A 3 ° B In both formulas 3 ^ A and 3J Z1 f Z2, Z3, Z4, Z5, Zß, Z7 and Z8 are independently selected from CR2, N, O, S or N-Ri and as mentioned above one of Z? -Z8 is a carbon atom to which the rest of the molecule is attached. And Y2, Y3 and Y4 can be C or N.

The layout and size of the ring (5-6-6). 4-C In the formulas 4-A, 4-B and 4 ^ C Z-¡, Z2, Z3, Z, Z5, Zß, Z7 and Z8 are independently selected from CR2, N, O, S or -R and as mentioned above one of ZrZß is a carbon atom to which the rest of the molecule is attached. Y1 (Y2, Y3 and Y are independently C or N.

The arrangement and size of the ring [5-5- (non-aromatic)].

In both formulas 5-A and 5-B Z1 f Z2, Z3 and Z, are independently selected from CR2, N, O, S or N-Rt and as mentioned above one of them is a carbon atom to which the rest of the molecule is attached. Y1t Y2, Y3 and Y are independently C or N. Wi, W2 and W3 are independently selected from CR4R4, S (O) r (r = 0-2), O, N-Ri with the proviso that no formation can occur link SS, SO or OO to form a saturated ring; and t = 1 to 3.

The arrangement and size of the ring [5-6- (non-aromatic)] In the formulas 6-A. 6B and 6; C Z1 f Z2, Z3, Z and Z5 are independently selected from CR2, N, O, S or N-Ri and as mentioned above one of Z1-Z5 is a carbon atom to which the remainder of the molecule is attached. Y and Y2 are independently C or N. W ,, W2 and W3 are independently CR4R4? S (O) r (r = 0-2), O, or -Rt with the proviso that no bond formation S-S, S-O or O-O can occur to form a saturated ring; and t = 1 to 3.

The arrangement and size of the ring [5-. { non-aromatic) -5].

In the formulas ° and 7; B Z Z2, Z3, Z4, Z5 and Z6 are independently selected from CR2, N, O, S or N-RT; one of Zi-Zß is a carbon atom to which the rest of the molecule is attached. Y1, Y2, Y3 and Y4 are independently C or N. W1 t and W2 are independently selected from CR R4? S (O) r (r = 0-2), O, N-RT with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; and t = 1 to 3.

The arrangement and size of the ring [5- non-aromatic) -6J. 8-B In the formulas 8 ^ and 8; B Zu Z2, Z3, Z ,,, Z5, Zß and Z7 are independently selected from CR2, N, O, S or N-R1 and as mentioned above one of the Z Z7 is a carbon atom to which the rest of the molecule is attached. Y1, Y2, Y3 and Y4 are independently C or N. W1? and W2 are independently CR4R4, S (O) r (r = 0-2), O, N-Ri with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; and t = 0 to 3.

The arrangement and size of the ring [5- (non-aromatic) - (n © aromatic)]. 9-A 94 In the formulas 9-A and 9-B Z1 f Z2 and Z3, they are independently selected from CR2, N, O, S or N-R ^ one of Z Z3 is a carbon atom to which the rest of the molecule is attached. Y1 (and Y are independently C or N; Y2 and Y3 are independently CH or N; W ,, W2, W3, W4 and W5 are independently CR4R4, S (O) r (r = 0-2), O, NR with the condition that no SS, SO or OO bond formation can occur to form a saturated ring, and t = 0 to 2 and u = 1 to 3.

The layout and size of the ring (6-5-6) 10-B In the formulas 10-A and 10-B Z, Z2, Z3, Z, Z5, Zß, Z7, Z8 and Z9 are independently selected from CR2, N, O, S or N-RT; and as mentioned above one of the Z1-Z9 is a carbon atom to which the rest of the molecule is attached. Y1, Y2, Y3 and Y4 are independently C or N.

The layout and size of the ring (6-6-6) 1 J In the formula 11 -A. 11B and 11-C Zu Z2, Z3, ZA, Z5, Z6, Z7, Z8, Z9 and Z10 are independently CR2, N, O, S or N-R1; one of Z Z10 is a carbon atom to which the rest of the molecule is attached. Y ^ Y2, Y3 and Y4 are independently C or N.

The arrangement and size of the ring [6-5- (non-aromatic)] 12-A 92-B In the formulas 12-A and 12-B Z1, Z2, Z3, Z4 and Z5 are independently selected from CR2, N, O, S or NR ^ with the proviso that one of Z ^ Zs is a carbon atom to which the The rest of the molecule is attached. Y1t Y2, Y3 and Y are independently C or N; W ,, W2, and W3? are independently CR R4, O, N-R1 or S = (O) r (r = 0-2), with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; and t = 1-4.

The arrangement and size of the ring [6-6- (non-aromatic)] In the formulas 13-A. 13-B and 13-C Zi, Z2, Z3, Z, Z5 and Z6 are independently CR2, N, O, S or N-R? one of Zi-Zß is a carbon atom to which the rest of the molecule is attached. Yi, Y2, Y3 and Y4 are independently C or N; Wi, W2 and W3 are independently CRjR- », S (O) r (r = 0-2), OR, or N-Ri with the condition that no SS, SO or OO bond formation can occur to form a ring saturated; and t = 1 to 3.

The arrangement and size of the ring [6- (non-aromatic) -6] 14 «A 14-B In formulas 14-A, 14-B and 14-C Z1t Z2, Z3, Z-, Z5, Zß, Z7 and Z8 are independently CR2, N, O, S or NR? One of Z Z8 is an atom of carbon to which the rest of the molecule is attached. Yi, Y2, Y3 and Y4 are independently C or N; W?, And W2 are independently CR R, S (O) r (r = 0-2), OR, or N-Ri with the proviso that no SS, SO or OO bond formation can occur to form a saturated ring; and t = 1 to 2.

The arrangement and size of the ring [6- (non-aromatic) - (non-aromatic)] 1 > TO In formulas 15-A. 15-B and 15-C Z1 f Z2, Z3 and Z * are independently CR2, N, O, S or N-R ^ one of Z ^ is a carbon atom to which the rest of the molecule is attached. Y1 t Y2, Y3 and Y4 are independently C or N; W1, W2, W3, W and W5 are independently CR R, S (O) r (r = 0-2), OR, or N-Rt with the condition that no SS, SO or OO link formation can occur for form a saturated ring; t = 1 to 3 and u = 1 to 3.

The compounds according to the present invention have β-lactamase and antibacterial inhibitory properties and are useful for the treatment of infections in humans and animals. It should be noted that the compounds of the present invention, when used in combination with the β-lactam antibiotics will result in increased antibacterial activity (synergistic effects) against the organisms that produce the class D. The β-lactam antibiotics include penicillin antibiotics such as piperacillin, amoxicillin, ticarcillin, benzylpenicillin, ampicillin, sulbenicillin, other known penicillins and cephalosporins such as cefatrizine, cephaloridin, cephalothin, cefazolin, cephalexin, cephradine, other known cephalosporins, aztreonam and latamofex (Moxalactam) and carbapenems such as meropeneme and imipeneme . The most preferred compounds of this invention are used with piperacillin or amoxicillin which has a broad spectrum of activity against the Gram positive and Gram negative pathogens.

The compounds of the present invention may be delivered prior to, concurrent with, or subsequent to a β-lactam antibiotic ("co-administration"). By "supplying" is meant to include administering the compound directly or in vivo, for example pro-drugs. When the compounds of the present invention are coadministered with a β-lactam antibiotic, the ratio of the amount of the compounds to the amount of the β-lactam antibiotic can vary over a wide range. The ratio of the β-lactam antibiotic to the β-lactamase inhibitor can vary from 1: 1 to 100: 1. Preferably the ratio of the β-lactam antibiotic to the β-lactamase inhibitor is less than 10: 1. The composition of the present invention may be in a soluble form for oral administration (PO), intravenous (IV) or topical. The compositions of the invention may be in the form of tablets, capsules, creams, syrups, suspensions, sterile solutions suitable for injection or infusion. Preferably the compounds of the present invention are co-administered intravenously piperacillin or amoxicillin intravenously or orally.

The structural formula of the compound includes any tautomer, any stereoisomer (except where the stereochemistry is clearly known) and any crystalline form.

The following examples further illustrate the invention; they should not be considered as limiting the invention. It will be readily apparent to one skilled in the art that additional embodiments may be made that are still within the spirit and scope of the invention.

EXAMPLE 1 Preparation of (5R, 6Z) -6- (imidazor2.1-b1M.31benzothiazole-2-ylmethylene®!) 4-thia-1-azabicyclo3.2.01hept-2-ene-2-carboxylic acid Step 1: Ethyl imidazor2,1-b1-benzthiazoi-2-carboxylate: Ethyl bromopyruvate (9.8 g 50 mmol) is added drop wise to a stirred solution of 2-aminobenzothiazole (7.5 g, 50 mmol) in DMF (100 ml) at room temperature. After the addition, the reaction mixture is refluxed for 6 h. The reaction mixture is cooled to room temperature and quenched with ice water. The aqueous layer is neutralized with NH 4 OH and the separated solid is filtered. This is washed well with water and dried. The crude product obtained is taken in the next step without purification.

Solid coffee; Yield 10 g, 81%; M + H 248 pf 97 ° O Stage 2: lmidazor2.1-b1-benzthiazole-2-methanol: To a stirred solution of UAIH (2.0 g excess) in dry THF, imidazo [2,1-b] -benzthiazole-2-carboxylic acid ethyl ester (4.9 g 20 mmol) in THF (100 mL) is slowly added at 0 ° C. of the addition, the reaction mixture is stirred at room temperature for 1 h and quenched with saturated NH 4 Cl / NH 4 OH. The separated solid is diluted with chloroform / MeOH (3: 1) and filtered through a pad of Celite. The organic layer is washed once with saturated NaCl and dried over anhydrous MgSO. This is filtered and concentrated. The solid coffee that is obtained is taken to the next stage without purification. Yield: 3.8 g, 93%; M + H 205; mp 131 ° C.

Step 3: 2-Formyl-imidazor2.1-bT-benzthiazole: To a stirred solution of imidazo [2,1-b] -benzthiazole-2-methanol (2.04 g, 10 mmol) in methylene chloride (200 ml) is added activated MnO2 (15 g excess). The reaction mixture is stirred at room temperature for 24 hours and filtered through a pad of Celite. The reaction mixture is concentrated and the product is purified by column chromatography on silica gel by eluting with 75% ethyl acetate; Hexane Solid coffee; Yield: 800 mg 40%; M + H 203.

Step 4: 4-Nitrobenzyl-6-r (acetyloxyHimidazor2.1-bin.3Tbenzothiazol-2-yl) meaiC1 - @ - bromo-7-oxo-4-thia-1-azabicyclo3.2.0lhept-2-ene-2- carboxylate: 2-Formyl-imidazo [2,1-b] -benzthiazole (444 mg, 2.2 mmol) and a solution of dry THF (20 ml) of 4-nitro-benzyl ester of (5R.6S) acid are added successively. 6-Bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (772 mg, 2. mmol) to dry acetonitrile solution (15 mL) of MgBr2 anhydrous: etherate (619 mg, 2.4 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is heated to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate, and saline.

The organic layer is dried (MgSO4) and filtered through a Celifa pad. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to a column of silica gel, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is taken in the next step. Pale yellow amorphous solid; Yield: 850 mg, 67%; mp 69 ° C; M + H 630.

Step 5: Acid (5ffl. (6Z) -6- (lmidazori.2-pyri.31-benzothiazol-2-ylmethylene) -7-o ^ ® ° 4-thia ° 1-azabicyclo3.2.01hept-2-ene-2- carboxylic: Dissolve 4-Nitrobenzyl-6 - [(acetyloxy) (imidazo [2,1-b] [1,3] benzothiazole-2-ii) methyl] -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (500 mg, 0.79 mmol) in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn powder (5.2 g) is added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The precipitate is dissolved in acetonitrile and loaded onto a reverse phase column of HP-21. This is eluted with deionized water (2 L) and eluted at the end with 10% acetonitrile: water. Yield: 105 mg, 35%; like yellow crystals; mp 233 ° C; M + H 356. 1 H NMR (DMSO-d 6) d 6.51 (s, 1 H), 6.53 (s, 1 H), 7.09 (s, 1 H), 7.47 (t, 1 H, J = 7.5 Hz), 7.54 (t, 1 H, J = 7.5 Hz), 8.06 (t, 1 H), 8.62 (s, 1 H). EXAMPLE 2 Preparation of 5R.6Z) -6-r (7-methoxyimidazor-2-bin.31benzothiaz @ B-2-ylmethylene) -7-oxo-4-thia-1-azab-cyclor3.2.01hept- acid 2-ene-2-carboxylic @ Step 1: 7-Methoxyimidazof2.1-bl-benzthiazole-2-ethylcarboxylate: Ethyl 7-methoxyimidazo [2,1-b] -benzthiazole-2-carboxylate is prepared according to the procedure outlined in Example 1, (Step 1). Starting with 6-methoxy-2-amino benzothiazole (27 g, 0.15 mol) and ethyl bromopyruvate (39.9 g, 0.2 mol), 24 g (43% yield) of 7-methoxyimidazo [2,1-b] -benzthiazole Ethyl 2-carboxylate is isolated as a brown solid. (M + H) 277.

Step 2: 7-methoxy imidazor2.1 ° b1-benzthiazole-2-methanol: 7-Methoxy imidazo [2,1-b] -benzthiazole-2-methanol is prepared according to the procedure outlined in Example 1, (Step 2). Starting with ethyl 7-methoxyimidazo [2,1-bj-benzthiazole-2-carboxylate (12.5 g, 43.5 mmol) and LiAIH solution (43.5 ml, 0.5 M solution in THF), 4.0 g (40% yield) of the The alcohol derivative is isolated as a brown solid. (M + H) 235.

Step 3: 2-Formyl-7-methoxyimidazor2,1-b1-benzthiazole: 2-Formyl-7-methoxyimidazo [2,1-b] -benzthiazole is prepared according to the procedure outlined in Example 1, (Step 3). Starting with 7-methoxyimidazo [2,1-b] -benzthiazole-2-methanol (4.0 g 17 mmol) in methylene chloride / DMF (300 mL: 50 mL) and Active MnO2 (12 g, excess), 822 mg (21% Yield) of the aldehyde derivative is isolated as a brown solid. (M + H) 233.

Step 4: 4-Nitrobenzyl-6-f (acetyloxy) (7-methoxyimidazof2.1 ^ bip.31benzot? Azc i-ipmethyl1-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.0 lhept-2-ene-2-carboxylate: 2-Formyl-7-methoxyimidazo [2,1-b] -benzthiazole (822 mg, 3.5 mmol) and the dry THF solution (40 ml) of 4-nitro-benzyl ester of acid (5R.6S) are successively added. ) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1364, 3.54 mmol) to the dry acetonitrile solution (15 ml) of Anhydrous MgBr2: etherate (1.3 g, 5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is heated to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate, and saline. The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to a column of silica gel, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is carried to the next stage. Solid pale yellow amorous; Yield: 2.24 g, 95%; M + H 660.

Step 5: Acid (5R). (6Z -6-r (7-methoxyimidazon.2-Piri.31benzothiazol-2-ylmetna®BioM ° 7-oxo-4-thia-1-azabicyclo r3.2.01hept-2-ene -2-carboxylic: Dissolve 4-Nitrobenzyl-6 - [(acetyloxy) (7-methoxyimidazo [2,1-b] [1,3] benzothiazol-2-yl) methyl] -6-bromo-7-oxo-4-thia-1 -azabicyclo [3.2.0] hept-2-ene-2-carboxylate (659 mg, 1.0 mmol) in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn powder (5.2 g) is added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The precipitate is filtered and washed with H2O, MeCN, acetone to give the title compound. Yield: 68 mg, 23%; like yellow crystals; mp 284; M + H 386. 1 H NMR (DMSO-dβ) d 3.89 (s, 3 H), 6.58 (s, 1 H), 6.64 (s, 1 H), 7.14 (s, 1 H), 7.2 (dd, 1 H, J = 6.0 Hz ), 7.75 (d, 1 H, J = 3.0 Hz), 8.03 (d, J = 6.0 Hz 1 H), 8.62 (s, 1 H).

Example 3 Preparation of (5R.6Z) -6-r (7-chloroimidazor2.1-bir 3-benzothia8i-2-ylmethylene) -7-oxo-4-thia-1-azabicyclof3.2.01hept-2-ene-2 ° acid earboxlic © Stage 1: 7-chloroimidazor2.1-b1-benzthiazole-2-ethylcarboxylate: Ethyl 7-chloroimidazo [2,1-b] -benzthiazole-2-carboxylate is prepared according to the procedure as outlined in Example 1, (Step 1). Starting with 6-chloro-2-aminobenzothiazole (9.2 g, 50 mmol) and ethyl bromopyruvate (11.6 g, 60 mmol), 8.5 g (60% yield) of 7-chloroimidazo [2,1-b] -benzthiazole Ethyl 2-carboxylate is isolated as a brown solid. (M + H) 281.

Step 2: 7-chloroimidazor2.1-b1-benzthiazole-2-methanol: 7-Chloroimidazo [2,1-b] -benzthiazole-2-methanol is prepared according to the procedure outlined in Example 1, (Step 2). Starting from ethyl 7-chloroimidazo [2,1-b] -benzthiazole-2-carboxylate (9.0 g, 32.1 mmol) and LiAIH4 (4.0 g, excess), 5.5 g (72% yield) of the alcohol derivative which is isolate as a brown solid, mp 166 ° C (M + H) 239.

Step 3: 2-Formyl-7-chloroimidazor2.1-b1-benzthiazole: 2-Formyl-7-chloroimidazo [2,1-b] -benzthiazole is prepared according to the procedure outlined in Example 1, (Step 3). Starting with 7-chloroimidazo [2,1-b] -benzthiazole-2-methanol (4.0 g 16.8 mmol) in methylene chloride / MeOH (300 mL: 50 mL) and active MNO2 (20 g, excess), 2.2 g ( 55% Yield) of the aldehyde derivative which is isolated as a brown solid. (M + H) 236.

Step 4: 4-Nitrobenzyl-6-r (acetyloxy) (7-chloroimidazof2,1-blM.3lbenzothiazo! L-2-yl) methyl-1-6-bromo-7-oxo-4-thia-1-azabiciclof3.2.01hept -2-ene-2-carboxylate: 2-Formyl-7-chloroimidazo [2,1-b] -benzthiazole (270 mg, 1.14 mmol) and the dry THF solution (20 ml) of 4-nitro-benzyl ester of (5R, 6S) acid are added successively. ) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (500 mg, 1.14 mmol) to the dry acetonitrile solution (15 ml) Anhydrous MgBr2: O (Et) 2 (390 mg, 1.5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous solution of citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a Celifa pad. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 495 mg, 65%; M + H 665.

Step 5: (5R 6Z) -6-r (7-chloroimidazori.2-pip.31-benzothiazo! -2-oxo-4-thia-1-azabicyclo-r3.2.01hept-2-ene-2-carboxylic acid; 4-Nitrobenzyl-6 - [(acetyloxy) (7-chloroimidazo [2, 1-b] [1, 3] benzothiazol-2-yl) methyl-6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (450 mg, 0.67 ppmol) are dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn powder (5.2 g) is added rapidly with a 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by HP21 resin reverse phase column chromatography. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 80 mg, 18%; like yellow crystals; mp 240 ° C; (M + H + Na) 412. 1 H NMR (DMSO-dβ) d 6.6 (s, 2H), 7.1 (s, 1 H), 7.62 (dd, 1 H), 8.11 (d, 1 H), 8.2 (s, 1H), 8.6 (s, 1 HOUR).

EXAMPLE 4 Preparation of (5R) Acid, (6Z -6-lmidazori.2-a1-quinolin-2-ylmethylene-7-oxo-tetia, 3 ° azabicyclo3.2.01hept-2-ene-2-carboxylic acid Smidazo [1,2-a] quinolino = 2-carba! Dehyde Imidazo [1,2-a] quinoline-2-carbaldehyde is prepared by the method of Westwood and colleagues (J. Med. Chem. 1988, 31, 1098-1115).

Stage 1: 4-nitrobenzyl ester of (5 6ftS) -6-r (ftS) -acetoximidazoyl-1-L-2-aquinolin-2-ylmethin-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept-2 -eno-2-carboxylic acid: Imidazo [1,2-a] quinoline-2-carbaldehyde (1.09 g) and dry THF solution (75.5 ml) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-acid are successively added. oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (2.22 g) to dry acetonitrile solution (75.5 ml) of anhydrous MgBr2 (2.5 g) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (1.85 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is heated to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate, and saline. The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to a column of silica gel, then the column is eluted with CHCl3-acetone (1/0 ~ 95/5). The collected fractions are concentrated under reduced pressure followed by recrystallization of CHCl3-Et2O to give the title compound as an isomer (pale yellow crystals, yield: 1.3 g, 38%).

H NMR (CDCl 3) d 2.37 (s, 3 H), 5.29 (d, 1 H, J = 13.5 Hz), 5.45 (d, 1 H, J = 13.5 Hz), 6.22 (s, 1 H), 7.14 (s, 1 H ), 7.46 ~ 7.52 (m, 3H), 7.56 (d, 1H, J = 9.6 Hz), 7.62 (d, 2H, J = 8.6 Hz), 7.64 ~ 7.69 (m, 1H), 7.83 (dd, 1H, J = 1.1, 7.9 Hz), 7.93 (d, 1H, J = 8.3 Hz), 7.99 (s, 1H), 8.25 (d, 2H, = 8.6 Hz).

Step 2: Acid (5ffl. (6Z) -6-lmidazoi-1,2-a1quinolin-2-lmethyl-ene-oxo-4-thia-azabicyclo3.2.01hept-2-ene-2-carboxylic acid: 4-Nitrobenzyl ester of (5, 6RS) -6 - [(RS) -acetoximidazo [1,2-a] quinolin-2-ylmethyl] -6-bromo-7-oxo-4-thia-1 acid is dissolved azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.3 g) in THF (17 ml) and acetonitrile (36 ml). Freshly activated Zn powder (5.2 g) is added rapidly with a 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, it is cooled to 3 ° C, and 1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The precipitate is filtered and washed with H2O, acetonitrile, and acetone to give the title compound, yield 297 mg, 38%, as yellow crystals mp 205 ° C. 1 H NMR (D 2 O) d 6.19 (s, 1 H), 6.36 (s, 1 H), 6.87 (s, 1 H), ß.96 (d, 1 H, = 9.5 Hz), 7.32 (d, 1 H, J = 9.5 Hz), 7.33 (s, 1 H), 7.44 ~ 7.57 m, 4H).

EXAMPLE 5 Preparation of (5?), (6Z) -6- (6,7-Dihydro-5H-cyclopentafcflimidazoyl-2-bis-3-thiazol-2-ylmethylene) -7-oxo-4-thia-1-azab-cyclor3.2.01hept acid -2-ene-2-ca: bo? Ííico Step 1: Preparation of 6.7-dihydro-5H-cyclopentadimidazor2.1 biri.31tiazofl ° 2-ethyl carboxylate.

A mixture of 2-chlorocyclopentanone (11.8 g, 100 mmol) and thiourea (8.0 g 101 mmol) is refluxed in ethanol: THF (1: 2) for 16 hrs. The reaction mixture is cooled to room temperature and the separated white solid is filtered. (9.0 g separated) This is dissolved in anhydrous ethanol (100 ml) and sodium methoxide (2.7 g, 51 mmol). To this is added ethyl bromopyruvate (10.0 g) and stirred at room temperature for 2 hrs. Then this is refluxed for 48 hrs. At the end the reaction mixture is cooled to room temperature and concentrated. The residue is extracted with chloroform and washed well with water. The product is purified by silica gel column chromatography by eluting with 50% ethyl acetate: hexane. Semi-solid red; Yield: 3.0 g; M + H 237.

The ester is reduced with LiAIH and the resulting alcohol is oxidized with active MNO2. The aldehyde that is obtained is taken to the next stage.

Step 3: Preparation of 4-nitrobenzyl (5R? -6-y (acetyloxy) (6,7-dihydro-5H-cyclopentadimidazor2.1-byri-3-thiazol-2-yl) -6-bromo-7-oxo-4- thia-1 ° azabicyclo3.2.01hept-2-ene-2-carboxylate: 2-Formyl-6,7-dihydro-5H-cyclopenta [d] imidazo [2,1-b] [1,3] thiazole (600 mg, 3.1 mmol) and dry THF solution (20 ml) were successively added. 4-Nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.2 g, 3 mmol) to dry acetonitrile solution (15 ml) of anhydrous MgBr 2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° O The mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate, and saline. The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 850 mg, 45%; M + H 620 Step 4: Preparation of (5R) acid. (6Z) -6- (6,7-dihydro-5H-cyclopentaddimicazor.2.1-byri-3-thiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept -2-ene-2-carboxyno Dissolve 4-nitrobenzyl (5R) -6 - [(acetyloxy) (6,7-dihydro-5H-cyclopenta [d] imidazo [2,1-b] [1,3] thiazol-2-yl) -6- Bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (850 mg, 1.37 mmol) in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn powder (5.2 g) is added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by HP21 resin reverse phase column chromatography. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried.

Yield: 138 mg, 29%: as yellow crystals: mp 192 ° C: (M + H + Na) 367. 1 H NMR (DMSO-dβ) d 2.51 (m, 4H), 3.01 (m, 2H), 8.2 ( s, 1 H), 7.1 (s, 1 H), 6.55 (s, 1 H), 6.4 (s, 1 H).

Example 6 Preparation of sodium salt, (5R) -6- (lm-dazop.2-a1quinoxaline-2-iim368nol) 7-oxo-4-thia-1-azabicyclo f3.2.01hepto-2-ene-2 acid -carboxylic lmidazo [1,2-a] quinoxaline-2-carboxaldehyde Imidazo [1,2-a] quinoxaline-2-carboxaldehyde is prepared by the method of Wesdosod and colleagues (J. Med. Chem. 1998, 31, 1098-1115).

Step 1: p-Nitrobenzyl ester of (5R. 6RS) -6 - ((RS) -Acetoxy imidaz®lH.2-a1quinoxalin-2-ylmethyl) -6-bromo-7-oxo-4-thia-1 -zabicyclo R3.2.01hept-2-ene-2 ° carboxylic: A solution of dry acetonitrile (33 ml) of imidazo [1,2-a] quinoxaline-2-carboxaldehyde (505 mg) is added to a solution of dry acetonitrile (20 ml) of MgBr2 (1.1 g) under a nitrogen atmosphere. room temperature, and the mixture is stirred for 10 min. After the addition of dry THF solution (25 ml) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] ] hept-2-ene-2-carboxylic acid (931 mg), the mixture is cooled to -20 ° C and then triethylamine (0.8 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The mixture is stirred for 4 h at -20 ° C and treated with 4,4-dimethylamino pyridine (58 mg) and acetic anhydride (0.44 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 16 h at 0 ° O 10% aqueous citric acid solution (200 ml) is added to the reaction mixture and the aqueous layer is extracted with ethyl acetate (3x100). my). The organic layer is washed with water, saturated sodium hydrogen carbonate and saline, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CH2Cl2-acetone (50: 1), and the title compound is obtained as a diastereomeric mixture (78:22, pale brown foamy amorphous, 1.0 g, 68.9 g). %). 1 H NMR (CDCl 3) d 2.07 (s, 0.66H), 2.38 (s, 2.34H), 5.30 (d, 1 H, J = 13.5 Hz), 5.45 (d, 0.78H, J = 13.5 Hz), 5.48 ( d, 0.22H, J = 13.5 Hz), 6.24 (s, 0.78H), 6.46 (s, 0.22H), 6.63 (s, 0.22H), 7.18 (s, 0.78H), 7.50 (s, 0.78H) , 7.52 (s, 0.22H), 7.61 (d, 1.56H, J = 8.7 Hz), 7.63 (d, 0.44H, J = 8.8 Hz), 7.64-7.67 (m, 1H), 7.68-7.73 (m, 1H), 7.92-7.95 (m, 1H), 8.08 (s, 0.78H), 8.13-8.16 (m, 1 H). 8.24 (d, 1.56H, J = 8.7 Hz), 8.25 (d, 0.44H, J = 8.8 Hz), 8.33 (s, 0.22H), 9.05 (s, 0.78H), 9.09 (s, 0.22H).

Step 2: Sodium salt, acid (bR), (6Z) -6-imidazon.2-a1-anoxaiin-2-ylme 5; ol? ^ oxo-4-thia-1-azabicyclo3.2.01 hept-2-ene-2-carboxylic acid: P-Nitrobenzyl ester of (5R, 6RS) -6 - ((RS) -acetoxy imidazo [1,2-a] quinoxalin-2-ylmethyl) -6-bromo-7-oxo-4-tiane is added. 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (951 mg) and 10% Pd-C (50% moisture, 477 mg) to a mixture of THF (48 ml) and 0.5 mol / l L of phosphate buffer (pH 6.5, 48 ml). The mixture is hydrogenated at 400 kPa at room temperature for 4 h. The reaction solution is filtered and the Pd-C is washed with water and n-butanol. The reaction mixture is cooled to 0 ° C and 1 N NaOH is added to adjust the pH to 8.5. The aqueous layer is separated and then the organic layer is extracted with water. The combined aqueous layer is concentrated to 57 g and applied to Diaion HP-21 resin column chromatography (60 mL, Mitsubishi Kasei Co. Ltd.). After absorption, the column is eluted with water and then a solution of acetonitrile: water of 5, 10, 15 and 20% (each of 60 ml). The combined fractions are concentrated under high vacuum at 35 ° C and lyophilized to give the title compound as a yellow amorphous solid, yield 148 mg (26.1%), mp 300 ° C (dec). 1 H NMR (D 2 O) d 5.92 (s, 1 H), 6.23 (s, 1 H), 6.66 (s, 1 H), 7.11-7.22 (m, 3 H), 7.25 (d, 1 H, J = 7.9 Hz), 7.50 (s, 1H), 8.03 (s, 1 H): IR (KBr) 3413, 1748, 1592, 1553 crn'1; lmax (H2O) 340, 293, 237, 218 nm.

EXAMPLE 7 Preparation of (5R.6Z) -6-r (7-methylimidazor2.1-b1M.3? PenzotiazoD 2 ° illmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene acid -2-earboxilico Step 1: Ethyl 7-methylimidazor2.1-b1-benzthiazole-2-carboxylate: Ethyl 7-methylimidazo [2,1-b] -benzthiazole-2-carboxylate is prepared according to the procedure as outlined in Example 1, (Step 1). Starting with 6-methyl-2-amino benzothiazole (3.2 g, 20 mmol) and ethyl bromopyruvate (4.0 g, 20.4 mmol), 3.0 g (57% Yield) of ethyl 7-methylimidazo [2,1-b] -benzthiazole-2-carboxylate is isolated as a brown solid. (M + H) 261.

Step 2: 2-Formyl-7-methylimidazor2.1-b1-benzthiazole: To a stirred solution of ethyl 7-methylimidazo [2,1-b] -benzothiazole-2-carboxylate (4.0 g, 15.38 mmol) in dry THF at -78 ° C, add DIBAL (1M toluene solution) (16.0) mi, 16 mmol). The reaction mixture is stirred at -78 ° C and raised slowly to room temperature. The reaction mixture is stirred at room temperature for 30 minutes and quenched with saturated NH 4 Cl. The reaction mixture is extracted with chloroform and washed well with water. The organic layer is dried over anhydrous MgSO 4; it is filtered and concentrated. The residue is purified by bt SiO2 column chromatography on elution with chloroform: methanol (20: 1). Solid coffee; (M + H) 217; Yield: 800 mg (24%).

Stage 3: 4-Nitrobenzyl-6-r (acetyloxy-7-methylimidazor-2-bin.31-benzothiazol-2-aa) -pnetiB1-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene- 2-carboxylate: 2-Formyl-7-methylimidazo [2,1-b] -benzthiazole (432 mg, 2.0 mmol) and the dry THF solution (20 ml) of 4-nitro-benzyl ester of (5R, 6S) acid are added successively. ) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (772 mg, 2.0 mmol) to the dry acetonitrile solution (15 ml) of anhydrous MgBr2: O (Et) 2 (566 mg, 2.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous solution of citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 400 mg, 31%; M + H 645 Step 4: Acid (5R). (6Z) -6-r (7-methylimidazori.2-biri.31benzothiazol-2-ylmethiiepo) l-7 ° oxo-4-thia-1-azabiciclof3.2.01hept-2 -eno-2-carboxylic acid: Dissolve 4-Nitrobenzyl-6 - ((acetyloxy) (7-methylimidazo [2, 1-b] [1, 3] benzothiazol-2-y) methyl] -6-bromo-7-oxo-4-thia-1 azabicyclo [3.2.0] hept-2-ene-2-carboxylate (350 mg, 0.54 mmol) in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn powder (5.2 g) is added rapidly with a 0.5 M phosphate buffer (pH 6.5, 28 ml) The reaction vessel is covered with film to isolate it from light, the reaction mixture is stirred vigorously for 2 h at room temperature, the reaction mixture is filtered, cooled to 3 ° C, and 0.1 N NaOH is added to adjust the pH to 8.5.The filtrate is washed with ethyl acetate and the aqueous layer is separated.The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by HP21 resin reverse phase column chromatography.The column is initially eluted with deionized water (2 L) and finally with 10% acetonitrile: water.The fractions containing the product are collected and c Concentrate under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 110 mg, 55%; like yellow crystals; mp 178 ° C (Dec); (M + H + Na) 392. 1 H NMR (DMSO-d 6) d 8.56 (s, 1 H), 7.93 (d, 1 H), 7.83 (s, 1 H), 7.38 (d, 1 H), 7.07 (s, 1 H), 6.51 (S, 2 H), 2.42 (s 3H).

Step 4: Acid (5R 6Z) -6-r (7-methylimidazori.2-diri.31benzothiazoi-2-methyl-meth) 1-7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2 -carboxylic: (Procedure B) Dissolve 4-Nitrobenzyl-6 - [(acetyloxy) (7-methylimidazo [2, 1-b] [1, 3] benzothiazol-2-yl) methyl] -6-bromo-7-oxo-4-thia-1 azabicyclo [3.2.0] hept-2-ene-2-carboxylate (350 mg, 0.54 mmol) in THF (40 ml) and phosphate buffer with pH 6.5 (40 ml) and hydrogenated over Pd / C (10%) , 200 mg) with a pressure of 40 psi for 3 hours at room temperature. At the end, the reaction mixture is filtered through a pad of celite and washed with acetonitrile. The reaction mixture is concentrated to 40 ml and cooled to 0 ° C and the pH is adjusted to 8.5 by adding 1N NaOH. The product is loaded directly onto HP21 resin reverse phase column chromatography. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions are concentrated and the yellow solid is washed with acetone, filtered and dried. Yield: 110 mg, 55% as a yellow solid.

EXAMPLE 8 Preparation of sodium salt of (5R 6Z) -6- (4,5,6,7-tetrahydro-1,3-ene or 3β-8-tetraaza-cyclopentara-1-deno-2-ylmethylene) -7-oxo-4-thia-1 acid aza-biciclor3.2.01 [? @ pt-2 ° eno-2-carboxylic Stage 1: 5.6.7.8-Tetrahydro-M, 2,41-triazolone .5-alpyridin-2-ylamine The 12.7% HCl solution in ethanol (5.35 ml) and 10% Pd-C (50% moisture) (2.5 g) are added to the mixture of [1, 2,4] triazolo [1, 5-a] ] pyridin-2-ylamine (2.5 g) in ethanol (72 ml). The reaction mixture is hydrogenated at 400 KPa of H2 for 3 days at room temperature. The mixture is filtered and concentrated under reduced pressure. The residue is treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The title compound is obtained as a pale yellow solid (2.31 g, 90%). 1 H-NMR (400 MHz, CDCl 3) d 1.88-1.94 (m, 2H), 1.98-2.05 (m, 2H), 2.77 (t, 2H, J = 6.2 H?), 3.95 (t, 2H, J = 6.2 Hz), 4.09 (brs, 2H).

Stage 2: Ethyl ester of acid 4.5.6.7-Tetrahydro ° 1.3a.3b.8 ° [raaza-ciclopentaralindeno-2-carboxylic acid Ethyl bromopyruvate (10.23 g) is added to the mixture of 5,6,7,8-tetrahydro- [1,4] triazolo [1,5-a] pyridin-2-ylamine (5.8 g) in 1, 2-dimethoxyethane (320 ml). The reaction mixture is stirred for 5 hours at room temperature and concentrated to 100 mL under reduced pressure. The precipitate is obtained by addition of distilled ether (200 ml), followed by filtration. The precipitate is dissolved in ethanol (175 ml) and stirred for 20 hours at 110 ° C in a protective tube. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then eluted with ethyl acetate-methanol (1/1). The title compound is obtained as a pale yellow solid (7.56 g, 77%). 1 H-NMR (400 MHz, CDCl 3) d 1.42 (t, 3 H, J = 7.1 Hz), 2.14-2.25 (m, 4 H), 3.11 (t, 2 H, J = 6.1 Hz), 4.37 (t, 2 H, J = 5.7 Hz), 4.41 (q, 2H, J = 7.1 Hz), 7.57 (s, 1H).

Stage 3: 4.5.6.7-Tetrahydro-1, 3a, 3b, 8-tetraaza-cyclopentara1indeno-2-carbaie Tl iod 1.01 M diisobutylaluminum hydride in toluene (1.06 ml) is added dropwise to the solution of ethyl ester of 4,5,6,7-tetrahydro-1,3a, 3b, 8-tetraaza-cyclopenta [a] indene-2-carboxylic acid (100 mg) in dry THF (5 ml) at -78 ° C under a nitrogen atmosphere. The reaction mixture is stirred for 30 minutes at -78 ° C and treated with ethanol (ca. The mixture is warmed to 0 ° C and stirred for 1 h at 0 ° C. The reaction solution is diluted with ethyl acetate (20 ml), treated with 0.5 ml saturated ammonium chloride solution, and sonicated for ca . 5 minutes (until enough precipitate is deposited). The mixture is dried (Na2SO) and filtered through a pad of Celite. The filtrate is concentrated under reduced pressure. The residue is crystallized from dichloromethane and diethyl ether to give the title compound (47.4 mg, 58%). 1 H-NMR (400 MHz, CDCl 3) d 2.16-2.27 (m, 4 H), 3.14 (t, 2 H, J = 6.1 Hz), 4.39 (t, 2 H, J = 5.7 Hz), 7.53 (s, 1 H), 10.01 (s, 1H).

Step 4: 4-Nitro-benzyl ester of (5R. 6RS) -6- (RS) Acetoxy-r4.5.6.7 ° tetrahydro-1.3a.3b.8-tetraaza-cyclopentara1indeno-2-in-methyl) -6-bromo-7-oxo- ia ° 1 ° aza-biciclor3.2.01hept-2-ene-2-carboxylic 4,5,6,7-Tetrahydro-1,3a, 3b, 8-tetraaza-cyclopenta [a] indene-2-carbaldehyde (2.97 g) is added to the solution of dry acetonitrile (110 ml) of anhydrous MgBr 2 (4.45). g) under a nitrogen atmosphere at room temperature. The dry THF solution (110 ml) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2 -eno-2-carboxylic acid (2.97 g) is added to the reaction mixture, cooled to -20 ° C, and triethylamine (6.45 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. After the mixture is stirred for 1.2 h at -20 ° C, acetic anhydride (2.9 ml) is added in one portion. The reaction mixture is warmed to 0 ° C and stirred for 16.5 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with H2O and saline. The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, eluted with ethyl acetate-n-hexane (3/1) and then with ethyl acetate-methanol (5/1). The title compound is obtained as a brown amorphous solid (651.6 mg, 13%). 1 H-NMR (400 MHz, CDCl 3) d 2.10-2.24 (m, 4H), 2.29 (s, 3H), 3.04-3.07 (m, 2H), 4.28-4.32 (m, 2H), 5.27 (d, 1H, J = 13.7 Hz), 5.43 (d, 1H, J = 13.7 Hz), 6.19 (s, 1H), 6.91 (s, 1H), 7.01 (s, 1H), 7.49 (s, 1H), 7.59-7.62 ( m, 2H), 8.23-8.25 (m, 2H).

Step 5: Sodium salt of acid (5R6Z) -6- (4.5.6.7-tetrahydro-1.3a.3b.8-tetraaza-cyclopentaralindene-2-ylmethylene) -7-oxo-4-thia-1-aza- biciclor3.2.Qlhept-2-en? "2 ° carboxylic 4-Nitro-benzyl ester (5R, 6RS) -6- is dissolved. { (RS) -Acetoxy- [4,5,6,7-tetrahydro-1,3a, 3b, 8-tetraaza-cyclopenta [a] indeno-2-yl] -methyl} -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (643.6 mg) in THF (9 mL) and acetonitrile (4.2 mL). The freshly activated Zn powder (2.57 g) and 0.5 M phosphate buffer (pH 6.4, 13.2 ml) are added to the reaction mixture. The reaction vessel is covered with film to isolate it from light. The mixture is stirred vigorously for 2 h at room temperature. The mixture is cooled to 3 ° C, and aqueous 1N NaOH solution is added to adjust the pH to 7.5. The reaction solution is mixed with ethyl acetate and filtered through a pad of Celite. The pad is washed with water. The aqueous layer is concentrated at 20 mL under high vacuum at 35 ° C. The concentrate is applied to Diaion HP-21 resin column chromatography (60 mL, Mitsubishi Kasei Co. Ltd.). After absorption, the column is eluted with water and then with 2.5-10% acetonitrile-water. The combined fractions are concentrated under high vacuum at 35 ° C and lyophilized to give the title compound as a yellow amorphous solid (68 mg, 18%, pH 7.4). mp 175 ° C (dec); 1 H-NMR (400 MHz, D 2 O) d 1.85-2.03 (m, 4H), 2.85-2.99 (m, 2H), 4.07-4.14 (m, 2H), 6.34 (s, 1H), 6.74 (s, 1H) , 6.76 (s, 1H), 7.28 (S, 1H).

EXAMPLE 9 PREPARATION OF ACID (5R.6E) -6-r (10-BENCIL-11-OXO-10.11- DIHYDRODIBENZ? RB.Flf1.4lOXAZEPIN-8-IEMETHYLENE1-7-OXO-4-TIA-1- AZABICICLOf3.2.01 HEPT-2-ENO-2-CARBOXLICO Stage 1: Preparation of 8- (hydroxymethyl) dibenzorb, flri, 4loxazepin-11 (10ffl Qiiia Lithium aluminum hydride (11 mL, 11 mmol) is slowly added to the solution of methyl ester of 11-oxo-10,11-dihydro-dibenzo acid [£ > , /] [1,4] oxazepine-8-carboxylic acid (1346 g, 5 mmol) in THF under N2 at room temperature. The reaction mixture is stirred for 1 hour and 45 minutes then quenched with 2N HCl until the pH value reaches 2-3. The whole THF is removed by rotary evaporation, and the reaction mixture is extracted with ethyl acetate for five times, the organic layer is dried with sodium sulfate and filtered and concentrated. The desired compound (white solid) is obtained with 46% yield.

Stage 2: Preparation of 11-oxo-10,11-dihydrodibenzorb.flH.41oxazepima-§ ° carbaldehyde 8- (Hydroxymethyl) dibenzo [b, f] [1,4] oxazepin-11 (10H) -one (0.241 g, 1 mmol) in acetonitrile is added to molecular sieves (1 g) under N2 at room temperature and then also 4-Methylmorpholine N-oxide (0.175 g, 1.5 mmol) is added in the reaction mixture. After stirring the mixture for 10 minutes, tetrapropylammonium perruthenate (0.0176 g, 0.05 mmol) is added and the reaction is monitored by t.l.c. until completed. The reaction mixture is diluted with 10 ml of ethyl acetate and flashed through a column of small silica gel. Collect all the ethyl acetate containing the desired material, extract the organic layer with 1 N HCl and also wash with saline. The organic layer is dried over sodium sulfate and filtered and concentrated. The desired compound (white solid) is obtained with 83% yield.

Stage 3: Preparation of 10-benzyl-11-oxo-10.11-dihydro-dibenzofb.fin.41oxaa (E! Pina ° 8-earbaldehyde: Anhydrous potassium carbonate (0.207 g, 1.5 mmol) and benzyl bromide (0.205 g, 1.2 mmol) are added to a solution of 11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepine-8-carbaldehyde (0.240 g, 1 mmol) in acetonitrile under N2 at room temperature. The reaction mixture is then refluxed for 4 hours, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate and filtered through a pad of magnesol and concentrated. Purify with silica gel column and 50% ethyl acetate in hexane. The desired compound is obtained (light yellow oil) with 63% yield.

Step 4: Preparation 4-nitro-benzyl ester of 6-facetoxH10-ben l] - @ xo 10.11 -dihydro-dibenzorb.fip.4loxazepin-8-yl) -metill-6-bromo-7oxo ° 4-tia -1-aza-bicyclo3.2.01hept-2-ene-2-carboxylic acid; 10-Benzyl-11-oxo-10,11-dihydro-dibenzo [b, f] [1,4] oxa-epine-8-carbaldehyde (0.250 g, 0.759 mmol) in acetonitrile is added to magnesium bromide (0.419 g) 2.28 mmol) low N2 at room temperature. The dry THF solution of 4-nitrobenzyl ester of acid (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (0.292 g, 0.758 mmol) is then added to the mixture. After 15 minutes the reaction mixture is cooled to -20 ° C, and triethylamine (0.317 mL, 2.27 mmol) is added. The reaction bottle is covered with foil to isolate it from light. After 4 hours at -20 ° C, treated with acetic anhydride (0.358 mL, 3.795 mmol) and DMAP (0.00927 g, 0.0759 mmol). The reaction mixture is heated to 0 ° C and placed in the freezer overnight.

The reaction solution is concentrated and dissolved with ethyl acetate and washed with 5% aqueous citric acid solution, saturated NaHCO3, water and saline. The organic layer is dried over sodium sulfate and filtered and concentrated. Purify with silica gel column and ethyl acetate / CH 2 Cl 2 1: 15. The desired compound is obtained (light yellow oil) with 41% yield.

Step 5: Preparation of sodium salt, 6- (10-benzyl-11-oxo-10.11-dihydro-dibenzorb.firi.41oxazepin-8-ylmethylene) -7-oxo-4-thia-1-aza-bicyclof3 acid. 2.01hept ° 2 ° © no ° 2 ° carboxylic: A solution of 0.5M phosphate buffer (pH 6.5) is added to the solution of 4-nitro-benzyl ester of 6- [acetoxy- (10-benzyl-11-oxo-10,11-dihydro-dibenzo [b]] , f] [1,4] oxazepin-8-yl) -methyl] -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (0.210 g , 0.273 mmol) in THF, followed by 10% Pd-C (0.0546 g). The reaction mixture is then hydrogenated at 40 psi for three hours. It is filtered through a pad of Celite and the THF is removed by rotary evaporation, the mixture is extracted with ethyl acetate and washed with water and saline. The organic layer is dried with sodium sulfate and filtered and concentrated. The NaHCO3 is dissolved with a minimum amount of water and added to the reaction mixture together with a small amount of ethyl acetate until the pH value reaches 7-8., the ethyl acetis evapor. Purify with reverse phase column (MCI Gel CHP20P) with varying amounts of acetonitrile (0% -20%) in w. The acetonitrile and w are removed by rotary evaporation, and the compound is freeze dried. The desired mial is obtained (yellow solid) with 24% yield. Mp: 179 ° O 1 H NMR (DMSO) d 1,755-1,825 (s 1H), 2,497-2,506 (d, 2H), 5,243-5,434 (m 2H), 6,516-6,770 (m, 1 H), 7,039- 7792 (m, 11 H).

EXAMPLE 10 Preparation of 6- (5-ethoxy-7.8-dihydro-6H-3.4.8b-triaza-as-i? T) dace? P? 2 -tymethylene) -7-oxo-4-thia-1- acid aza-biciclof3.2.01hept-2-ene-2-earboxílico STAGE 1: PREPARATION OF 4-ETOXI-6.7-DIHYDRO-5H-CICLOPENTAPIRIMIDIN-2-ILAMINE (SM: Ross, L., Goodman, L., Baker, B.R.A. Am. Chem. Soc. 1959, 81, 3108) 5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine are dissolved in 200 ml of xylene and 30 ml of absolute ethanol. Then 6.8 grams of sodium ethoxide are added and the mixture is refluxed for 3 hours. Then the solvent is removed in vacuo and 100 ml of water are added to the residue. Filter and wash the cake with water (50 ml). The solid is subjected to additional vacuum to dry it for several hours. The desired product weighs 5.3 grams (98% yield). Pf: 133.8 ~ 134.9 ° C. 1 H-NMR: (300 MHz, CDCl 3) d 6.23 (s, NH 2), 4.28 (quartet, 2 H, J = 6.9 Hz), 2.6 (m, 2 H), 1.93 (m, 2 H), 1.27 (t, CH 3, J = 6.9 Hz); MS: 180.0 (M + H).

Step 2: Preparation of ethyl ester of 5-Ethoxy-7.8-dihydro-6H-3.4.8b asbestos-indacene-2-carboxylic acid 5.2 grams (29 mmol) of 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine are dissolved in 100 ml of dry THF. Bromopyruvate (5.4 ml) is added dropwise for five minutes. The mixture is stirred at 23 ° C for one hour. This is then filtered and washed with ether to give 8.7 grams of solid. This solid is then dissolved in 50 ml of ethanol and refluxed for two hours. The reaction mixture is cooled to room temperature and partitioned between 350 ml chloroform and 200 ml saturated sodium bicarbonate. The organic layer is separated and dried over magnesium sulfate. The drying agent is filtered and concentrated to give 6.5 grams of the product.

MP: 168.6-168.7 ° C. 1 H-NMR: (300 MHz, CDCl 3) d 7.69 (s, 1H), 4.50 (quartet, 2H, J = 7.2 Hz), 4.40 (quartet, 2H, J = 7.2 Hz), 3.11 (t, 2H, J = 9.6 Hz), 2.88 (t, 2H, J = 9.6 Hz), 2.88 (m.2H), 1.43 (t, 2H, J = 7.2 Hz) .: MS: 276.2 (M + H).

STAGE 3: PREPARATION OF 5-ETOXI-7.8-DIHYDRO-6H-3.4.8B-TRIAZA-AS-INDACENO-2-CARBALDEHÍDO Dissolve 1,925 grams of 5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylic acid ethyl ester in 40 ml dichloromethane and then cool to -78 ° O Then add DIBAL (1 M, 21 mi, 3 eq.) In a period of five minutes. The reaction medium is then quenched with 2 ml of ethanol and partitioned between 350 ml of dichloromethane and 100 ml of 1 N sodium hydroxide. The aqueous layer is washed with another 150 ml of chloroform and the combined organic layer is dried over sulfate. of magnesium and filtered and concentrated to give the corresponding alcohol. The alcohol is then dissolved in 150 ml of dichloromethane and then 10 grams of manganese dioxide are added. The mixture is stirred at 23 ° C for two hours. The reaction mixture is then filtered through a pad of celite and concentrated to give 1.1 gram (68%) of the desired aldehyde.

Pf: 237.2-237.3 ° C 1 H-NMR: (300 MHz, CDC13) d 9.94 (s, 1 H, CHO), 8.39 (s, 1 H), 4.46 (quartet, 2H, J = 7.2Hz), 3.2 (m, 2H, CH2), 2.85 (m, 2H, CH2), 2.24 (m, 2H, CH2), 1.38 (t, 3H, CH3, J = 7.2Hz); MS: 232.1 (M + H).

Step 4: Preparation of 4-nitro-benzyl ester of 6-facetoxy acid-5S-β-7-dihydro-6H-3.4.8b-triaza-as-indacen-2-yl) -metill-6 bromo-7-oxo-4-thia-1-aza-bicyclo3.2.01hept-2-ene-2-carboxylic It is added to 30 ml of an acetonitrile solution of 5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde (693 mg, 3 mmol) 1.03 grams of etherate magnesium bromide. The mixture is stirred at 23 ° C for half an hour. A solution of 30 ml dry THF is then injected with the 4-nitro-benzyl ester of 6-Bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2. -carboxylic (1155 grams, 1 eq.) for one minute and the reaction mixture is then cooled to -20 ° O. Triethylamine (0.7 ml, eq.) is then injected and the reaction mixture is stirred for five hours at -20. ° O Acetic anhydride (0.377 ml, eq.) Is then injected and the reaction mixture is left at 0 ° for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, and 100 ml of saline. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 1.1 grams of the product.

PF: 118.7-119.1 ° C H-NMR: (300 MHz, CDCl 3) d 8.35 (d, 2H, J = 11Hz), 7.63 (m, 2H), 7.41 (d, 1H, J = 6.9Hz), 7.08 (d, 1H, J = 11Hz), 6.47 (s, 1H), 5.55 (4H, CH2), 4.54 (m, 2H), 3.09 (m, 2H), 2.93 (m, 2H) ), 2.32 (m, 2H), 1.41 (t, J = 9.6Hz); MS: 660.1 (M + H).

Step 5: Preparation of acid 6- (5-ethoxy-7.8-dihydro-6H-3.4.8b-triaza-as-iii dacen ° 2 ° illmethylene) -7-oxo-4-thia-1-aza-bicyclo3.2.01 hept-2-ene-2-carboxylic 4-Nitro-benzyl ester of 6- [acetoxy- (5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl) -methyl] -6 is suspended. -bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.03 grams, 1565 mmol) in 20 ml of THF and 20 ml of aqueous phosphate buffer at pH = 6.5. The mixture is then subjected to 45 psi of hydrogen for two hours. Then it is filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution is then cooled to zero degrees and basified to pH = 8 with 1N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% ~ 25% acetonitrile and water. The water is then removed by concentrating in vacuo and 100 mg of the product is collected.

PF: > 250 ° or H-NMR: (300 MHz, CDCl 3) d 7.52 (s, 1H), 6.95 (s, 1H), 6.54 (s, 1H), 4.73 (m, 2H), 3. 06 (m, 2H), 2.84 (m, 2H), 2.27 (m, 2H), 1.43 (t, 3H); MS: 383.2 (M + H).

EXAMPLE 11 Sodium salt, (5R.6E &Z) -7-oxo-6- (4H.10H-pyrazolor5.1-cin.41benzox @ z @ pin-2-ylmethylene) -4-thia-1-azabicyclo3 acid .2.0lhept-2-ene-2-carboxylic acid.

STAGE 1: Preparation of 1- (2-FLUOROBENCIL) -1H-PIRAZOL-3.5-DICARBOXYLATE Benzyl 2-fluorobromide (2.0 ml, 16.58 mmol) is added to a mixture of diethyl 3,5-pyrazolodicarboxylate (3.01 g, 14.18 mmol), Cs 2 CO 3 (5.57 g, 17.1 mmol), and acetonitrile (140 ml) under N 2. . It is heated at 60 ° C for two hours and then cooled to room temperature. Filter and concentrate the reaction solution. Water (~ 200 ml) is added to the resulting residue and extracted with EtOAc. The organics are washed with water and saline. The organics are dried over sodium sulfate and filtered and concentrated. Diethyl 1- (2-fluorobenzyl) -1H-pyrazole-3,5-dicarboxylate (light yellow oil) is obtained in quantitative yield.

STAGE 2: Preparation of 1- (2-FLUOROBENCIL) -1H-PIRAZOL-3,5-METANODIOL A 1M solution of DIBAL-H in THF (90 mL, 90 mmol) is added to a solution of diethyl 1- (2-fluorobenzyl) -1H-pyrazole-3,5-dicarboxylate (4.80 g, 14.99 mmol) in CH 2 Cl 2 (90 mi) at 0 ° C under N2. After two hours it is quenched with NH 4 Cl (ac) and a suspension is formed. Filter and extract with EtOAc and wash with saline. The organics are dried over sodium sulfate and filtered and concentrated. Purify with silica gel column and 5% MeOH in CH2CL2. 3.4 g of the diol compound (clear oil) is obtained in 96% yield.

Step 3: Preparation of 4H.10H-pyrazolor-5,1-c1H.41-benzoxazepine-2-carbazine The compound diol (3.83 g, 16.21 mmol) in HMPA (24 mL) is added to a suspension of NaH (60%, 1.34 g, 33.5 mmol) in toluene (330 ml) under N2. It is heated rapidly to 95 ° C for three hours and cooled to room temperature. Quench with water and extract with EtOAc. The organics are washed with water and saline. The organics are dried over sodium sulfate and filtered and concentrated. Purify with silica gel column and 2% MeOH in CH2Cl2. 4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepin-2-ylmethanol (white solid) is obtained. Yield: 0.71 g 20%. 4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepin-2-ylmethanol (0.71 g, 3.28 mmol), 4-methylmorpholine N-oxide (1 / 198g, 10.23 mmol), sieves are placed together molecular (powder, 4 angstroms) (3.32 g), and acetonitrile (0.07M) under N2. Tetrapropylammonium perruthenate (0.113 g, 0.322 mmol) is added and after three hours the reaction solution is filtered through celite and concentrated. Purify with silica gel column and EtOAc / Hexane 1: 1. 4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepine-2-carbaldehyde (white solid) is obtained. Yield: 0.31 g 44%.

Step 4: Preparation of 4-nitro-benzyl ester of 8-racetoxK4H acid, 10H-pyrazolor5.1-c1f1.41-benzoxazepine-8-yl) -methyl-6-bromo-7-oxo-4-thia-1-aza-bicyclo3 .2.01hept-2-ene-2-carboxylic acid: Add 4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepine-2-carbaldehyde (0.19 g, 0.887 mmol) in acetonitrile (14 ml) to MgBr 2 (0.49 g, 2.66 mmol) under N. After 25 minutes, 4-nitri-benzyl ester of 6-Bromo-7-oXo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (0.342 g, 0.888 mmol.) In THF (14 ml). After 15 minutes the reaction is cooled to -20 ° C. Ten minutes later Et3N (3 eq) is added and the reaction is placed in the dark. After 6.5 hours Ac2O (0.42 ml, 4.45 mmol) and DMAP (0.011 g, 0.0900 mmol) are added. It is heated to 0 ° C and placed in a freezer overnight. The reaction solution is concentrated and the resulting residue is taken up in EtOAc. Wash with 5% citric acid (ac) and saturated NaHCO3 (aC). Additionally it is washed with water and saline solution. The organics are dried over sodium sulfate and filtered and concentrated. Purify with prep plates of silica gel and 1: 2 EtOAc / Hexane. The condensation product (rubber / yellow solid) is obtained. Yield: 0.31 g, yield 54%.

Step 5: Sodium salt, acid (5R.6E &Z) -7-oxo-6- (4H.10H-pyrazolor5.1 ° cip.41benzoxazepin-2-ylmethylene) -4-thia-1-azabiciclof3.2.01hept -2 ° ene-2-carboxylic acid: Step 6: A 0.5M phosphate buffer solution (pH 6.5) (18 mL) is added to a solution of the condensation product (5) (0.300 g, 0.468 mmol) in THF (18 mL). Pd on Carbon (0.102 g) is added and the reaction mixture is hydrogenated at 40 psi for two hours. It is filtered through celite and the THF is removed by rotary evaporation. Extract with EtOAc. The organics are dried over sodium sulfate and filtered and concentrated. NaHCO3 (0.08 g, 0.952 mmol) is dissolved in a minimum amount of water and added to the concentrated organics together with a small amount of EtOAc. Filter and stir EtOAc by rotary evaporation. Purify with reverse phase column (MCI Gel CHP20P) and various amounts of acetonitrile (0% to 15%) in water. Acetonitrile and most water are removed from the fractions collected by rotary evaporation. The residue is dried by freezing to obtain 41 mg of sodium salt, (5R, 6E) -7-oxo-6- (4H, 10H-pyrazolo [5,1-c] [1,4] benzoxazepin-2-acid. illmethylene) -4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, (6) (yellow solid) in 22% yield. The HPLC finds that the purity is 77% and the ratio of E / Z isomer is 3: 2. 1 H-NMR (d, DMSO-d 6) 5 366 (m, 4 H), 5,649 (m, 4 H), 6,326 (t, 2 H), 6,444 (s, 2 H), 6,551 (s, 2 H), 6,640 (s, 2 H) ), 6,810 (s, 2H), 6,974 (m, 2H), 7,249 (m, 2H), 7355 (m, 2H). m / z (M + H) 390.0.

Example 12 Sodium salt of (5R) acid. (6Z) -6- (5H-imidazor2,1-a1isondol-2-ylmethyleneD ° 7 ° @ xo-4 ° thia-1-aza-bicichlor3.2.01hept-2-ene-2-carboxylic Stage 1: Preparation of 5H-imidazor2.1-a1isoindol-2-carbaldehyd @ The solution of 2-bromo-3-isopropoxy-propene (4.97 g) in dry acetonitrile (3 ml) is added to the mixture of 3-amino-1H-isoindole (3.4 g) in dry acetonitrile (100 ml). The reaction mixture is stirred for 3.25 h at room temperature. Then add triethylamine (3.6 ml) to the mixture and heat to reflux for 2 h. The mixture is cooled to room temperature, diluted with ethyl acetate, and washed with 20% potassium hydrogen carbonate. After filtration through a pad of Celite, the organic layer is dried (MgSO) and concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then eluted with ethyl acetate-hexane (3/1 ~ 4/1). The crude compound is crystallized from ethyl acetate and n-hexane to give the title compound (1.04 g, 22%). 1 H NMR (400 MHz, CDCl 3) d 5.01 (s, 2H), 7.28-7.52 (m, 3H), 7.90 (s, 1H), 7.91-7.93 (m, 1H), 9.92 (s, 1H).

Step 2: Preparation of 4-nitro-benzyl ester (5R. 6RS) -6-r (RS) -Acetoxy gH ° imidazor 2,1-a1isoindol-2-yl) -metn-6-bromo-7-oxo -4-thia-1-aza-biciclor3.2.01l Tigtt ° 2 ° ene-2-carboxylic acid: 5H-imidazo [2,1-a] isoindol-2-carbaldehyde (736.8 mg) is added to the solution of dry acetonitrile (50 ml) of MgBr2 anhydride (1-8 g) under a nitrogen atmosphere at room temperature. The dry THF solution (50 ml) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2 acid -eno-2-carboxylic acid (1.55 g) is added to the reaction mixture, cooled to -20 ° C, and triethylamine (1.34 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (0.76 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 18 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with H20, saturated sodium hydrogen carbonate, and saline. The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then eluted with ethyl acetate-hexane (2/3 ~ 1/1). The title compound is obtained as two diastreous mixtures (5/1, a pale yellow amorphous solid, 1.8 g, 73%). 1 H NMR (400 MHz, CDCl 3) d 2.02 (s, 0.84 x 3 H), 2.27 (s, 0.16 x 3 H), 4.89-4.94 (m, 2 H), 5.29 (d, 1 H, J = 13.6 Hz), 5.47 (d, 1 H, J = 13.6 Hz), 6.18 (s, 0.16 x 1 H), 6.40 (s, 0.84 x 1 H), 6.42 (s, 0.84 x 1 H), 6.94 (d, 0.16 x 1 H) , J = 0.9 Hz), 7.18 (d, 0.16 x 1 H, J = 0.7 Hz), 7.35-7.48 (m, 3H), 7.51 (s, 0.84 x 1 H), 7.60-7.64 (m, 2H), 7.79-7.83 (m, 1 H), 8.23-8.27 (m, 2H).

Step 3: Sodium salt of acid (5R). (6Z) -6- (5H-imydazor-2-a1-quinol-2-ylr;: iepo: -7-oxo-4-thia-1-aza-bicyclo3.2.01hept-2-ene-2- carboxylic 4-Nitro-benzyl ester of (5R, 6RS) -6 - [(RS) -acetoxy- (5H-imidazo [2,1-a] isoindol-2-yl) -methyl] -6-bromine is dissolved. -7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.5 g) in THF (21 ml) and acetonitrile (9.8 ml). Freshly activated Zn powder (6 g) and 0.5 M phosphate buffer (pH 6.4, 30.8 ml) are added to the reaction mixture. The reaction vessel is covered with film to isolate it from light. The mixture is stirred vigorously for 2 h at room temperature. The mixture is cooled to 9 ° C, and one of 1 M NaOH is added to adjust the pH to 7.5. The reaction solution is mixed with ethyl acetate and filtered through a Celifa pad. The pad is washed with water and the aqueous layer is separated. The aqueous layer is concentrated to 25 mL under high vacuum at 35 ° O. The concentrate is applied to Diaion HP-21 resin column chromatography (100 mL, Mitsubishi Kasei Co. Ltd.). After absorption, the column is eluted with water and then with 5-15% acetonitrile-water. The combined fractions are concentrated under high vacuum at 35 ° C and lyophilized to give the title compound as an amorphous yellow solid (527 mg, 58%). Mp 170 ° C (dec); 1 H NMR (400 MHz, D 2 O) d 4.62 (s, 2 H), 6.27 (s, 1 H), 6.56 (s, 1 H), 6.78 (s, 1 H), 7.22-7.31 (m, 4 H), 7.52 (d. 1H, J = 6.7 Hz).

Example 13 Preparation of (5R.6Z) -6-r (5-methylimidazor2.1-biri.3lpenzotiazo [(2-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene acid) -2-carboxylic ©.

Step 1: Ethyl 5-methylimidazor2.1-b1-benzthiazole-2-carboxylate: Ethyl 5-methylimidazo [2,1-b] -benzthiazole-2-carboxylate is prepared according to the procedure as outlined in Example 1, (Step 1). Starting with 4-methyl-2-amino benzothiazole (8.0 g, 48.7 mmol) and ethyl bromopyruvate (14.0 g, 71.7 mmol), 6.0 g (45% Yield) of 5-methylimidazo [2,1-b] -benzthiazole -2-ethyl carboylate is isolated as a brown solid. (M + H) 261.

Step 2: 5-methylimidazor2.1-bl-benzthiazole-2-methanol: 5-Methyl imidazo [2,1-b] -benzthiazole-2-methanol is prepared according to the procedure outlined in Example 1, (Step 2). Starting with ethyl 5-methylimidazo [2,1-b] -benzthiazole-2-carboxylate (5.2 g, 20 mmol) and LiAIH4 solution (22 ml, 0.5 M THF solution), 3 g (69% yield) ) of the alcohol derivative which is isolated as a brown solid. (M + H) 219.

Step 3: 2-Formyl-5-methylimidazor2.1l-b1-benzthiazole: 2-Formyl-5-methylimidazo [2,1-b] -benzthiazole is prepared according to the procedure outlined in Example 1, (Step 3). Starting from 5-methyl imidazo [2,1-b] -benzthiazole-2-methanol (2.0 g 9.1 mmol) in methylene chloride / DMF (300 mL: 50 mL) and active MnO2 (12 g, excess), 700 mg (35% Yield) of the aldehyde derivative which is isolated as a brown solid. (M + H) 217.

Stage 4: 4-Nitrobenzyl-6-r (acetyloxy) (5-methylimidazor2,1-biri.31benz @ ftiazoB-2-yl) metin-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept -2-ene-2-carboxylate: 2-Formyl-5-methylimidazo [2,1-b] -benzthiazole (432 mg, 2.0 mmol) and the dry THF solution (40 ml) of 4-nitro-benzyl ester of (5R, 6S) acid are successively added. ) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (770 mg, 2 mmol) to the dry acetonitrile solution (15 ml) of anhydrous MgBr2: etherate (1.3 g, 5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3fS3 (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous solution of citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to a column of silica gel, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is carried to the next stage. Pale yellow amorphous solid: Yield: 270 mg, 20%: M + H 644.

Stage 5: (5R) (6Z) -6-r (5-methylimidazo-1,2-bin.31benzothiazole) Imetile to: 7 ^ oxo-4-thia-1-azabicyclo r3.2.01hept- 2-ene-2-carboxylic acid: Dissolve 4-Nitrobenzyl-6 - [(acetyloxy) (5-methylimidazo (2,1-b] [1,3] benzothiazol-2-yl) methyl] -6-bromo-7-oxo-4-thia-1 -azabicyclo [3.2.0] hept-2-ene-2-carboxylate (400 mg, 0.62 mmol) in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn powder (5.2 g) is added rapidly with buffer of 0.5 M phosphate (pH 6.5, 28 ml) The reaction vessel is covered with film to isolate it from the light, the reaction mixture is stirred vigorously for 2 h at room temperature, the reaction mixture is filtered, cooled to 3 °. C, and 1N NaOH is added to adjust the pH to 8.5.The filtrate is washed with ethyl acetate and the aqueous layer is separated.The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. filter and wash with H2O, MeCN, acetone to give the title compound Yield: 60 mg, 24%: as yellow crystals, mp 192: M + Na 392. 1 H NMR (DMSO-dβ) d 2.1 (s, 3 H), 6.5 3 (s, 2 H), 7.1 (s, 1 H), 7.34-7.36 (m, 2 H), 7.85 (m, 1 H), 8.58 (s, 1 HOUR).

Example 14 Preparation of (5R.6Z) -6-r (7-fluoroimidazor2.1-bip.3lbenzotiazoi-2-ylmethylene) -7-oxo-4-thia-1-azabiciclof3.2.01hept-2-ene-2 acid -carboxílic ©.

Stage 1: ethyl 7-fluoroimidazor2.1-bl-benzthiazole-2-carboxylate: Ethyl 7-fluoro-imidazo [2,1-b] -benzthiazole-2-carboxylate is prepared according to the procedure outlined in Example 1, (Step 1). Starting with 6-fluoro-2-amino benzothiazole (10.0 g, 59.5 m.mol) and ethyl bromopyruvate (17.4 g, 89.2 mmol), 3.0 g (19% yield) of 7-fluoro-imidazo [2,1-b] ] -benzthiazole-2-carboxylic acid ethyl ester is isolated as a brown semi-solid. (M + H) 265.

Step 2: 7-Fluoro-imidazor2.1-b1-benzthiazole-2-methanol: 7-Fluoro-amidezo [2,1-b] -benzthiazole-2-methanol is prepared starting from 7-fluoro-imidazo [2,1-bl-benzthiazole-2-carboxylic acid ethyl ester (2.64 g, 0.01 mol) and LiBH4 (50 mg) in THF at reflux temperature for 2 hrs. At the end, the reaction mixture is quenched with ice-cooled water and acidified with 10 N HCl. The reaction mixture is stirred for 1 h and neutralized with K2CO3. The separated residue is extracted with chloroform: methanol (3: 1) and dried over anhydrous MgSO 4. This is filtered and concentrated. The crude reaction mixture was found to be pure and carried to the next stage without any purification. Yield: 1.5 g (68%) Semi solid: M + H 223.

Step 3: 2-Formyl-7-fluoro-imidazor2.1-bl-benzthiazoi: 2-Formyl-7-fluoro-imidazo [2,1-b] -benzthiazole is prepared according to the procedure outlined in Example 1, (Step 3). Starting with 7-fluoro-imidazo [2,1-b] -benzthiazole-2-methanol (1.5 g 6.7 mmol) in methylene chloride / DMF (300 mL: 50 mL) and active MNO2 (12 g, excess), 1.1 g (78% Yield) of the aldehyde derivative is isolated as a brown solid. (M + H) 221.

Stage 4: 4-Nitrobenzyl-6-y (acetyloxy) (7-f1uoro-midazor2.1-biri.31benzothiazoi-2-yl) methyl-1-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept -2-ene-2-carboxylate: 2-Formyl-7-fluoro-imidazo [2,1-b] -benzthiazole (500 mg, 2.3 mmol) and dry THF solution (40 ml) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (875 mg, 2.3 mmol) to dry acetonitrile solution (15 ml) of anhydrous MgBr2: etherate (1.3 g, 5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with 5% aqueous solution of citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO 4) and filtered through a pad of Celite, the pad is washed with ethyl acetate, the filtrate is concentrated under reduced pressure, the residue is applied to a column of silica gel, then the column is concentrated. eiuye with ethyl acetate: hexane (1: 1) .The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is taken to the next stage.Pellow yellow amorphous solid Yield: 330 mg, 22%; M + H 649 Step 5: (5R. (6Z) -6-r (7-Fluoro-imidazori.2-brie.31-benzothiazol-2-yltrnetile®) 1-7o-oxo-4-thia-1-azabicyclo R3.2.01hept- 2-ene-2-carboxylic acid: Dissolve 4-Nitrobenzyl-6 - [(acetyloxy) (7-fluoro-imidazo [2,1-b] [1,3] benzothiazol-2-yl) methyl] -6-bromo-7-oxo-4-thia -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (710 mg, 1.07 mmol) in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn powder (5.2 g) is added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 1 N NaOH is added to adjust the pH to 8.5. The filter is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The precipitate is filtered and washed with H2O, MeCN, acetone to give the title compound. Yield: 80 mg, 19%: as yellow crystals; mp 200 (dec): M + Na 396. 1 H NMR (DMSO-dβ) d 6.53 (s, 1 H), 6.63 (s, 1 H), 7.1 (s, 1 H), 7.45 (t, 1 H), 8.04 (m, 1 H), 8.13-8.10 (m , 1H), 8.61 (s, 1H).

EXAMPLE 15 Preparation of (5R 6Z) -6- (5,8-Dihydro-6 H -amidazoiZ 11 -bpipyrazofO-diri.31-thiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01heptide 2-ene-2-carb @ xyllic Step 1: Preparation of 5.8-dihydro-6H-imidazor2.1-blpiranof4. ^ airi.3itiaz:: carboxylate A mixture of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in CCI (100 mL) at 0 ° C, SO2Cl2 (7.4 g, 55 mmol) is slowly added. After the addition, the reaction mixture is stirred at room temperature for 4 hrs and quenched carefully with ice water. The reaction mixture is washed well and dried over anhydrous MgSO 4. The organic layer is filtered and concentrated. The colorless oil: which is obtained is dissolved in THF / EtOH containing thiourea (4.0 g, 52 mmol) and refluxed for 8 hrs. At the end, the reaction mixture is cooled to room temperature and the separated, white solid 6,7-dihydro-4H-pyran [4,3-d] [1,3] thiazole-2-amine hydrochloride is filtered. Yield 4.5 g (47%); P.F. 115 ° C, (M + H) 157.

To a stirred mixture of 6,7-dihydro-4H-pyran [4,3-d] [1, 3] thiazol-2-amine hydrochloride (4.0 g, 20.8 mmol) is dissolved in anhydrous ethanol (100 ml) and sodium methoxide (1.1 g, 21 mmol). This is stirred at room temperature for 30 minutes and to this is added ethyl bromotivurate (10.0g) and stirred at room temperature for 2 hours. Then it is put under reflux for 48 hours. At the end the reaction mixture is cooled to room temperature and concentrated. The residue is extracted with chloroform and washed well with water. The product is purified by column chromatography on silica gel by eluting with 50% ethyl acetate: hexane. Red semi-solid; Yield: 3.1 g (59%) (M + H) 253.

The ester is reduced with LiBH4 and the resulting alcohol is oxidized with active MnO2. The aldehyde obtained is taken to the next stage.

Step 3: Preparation of (5R) -6-r (acetyloxy) (5.8-dihydro-6H-imidazor-2-1-1-yl 3-piperane 14.3-dl M.31 thiazol-2-yl) -6-bromo-7-oxo-4- thia-1-azabicyclo P.2.01 Per 1 v ene-Zea rboxi lato 4-nitrobenzyl: 2-Formyl-5,8-dihydro-6H-imidazo [2.1-b] pyran [4.3-d] [1.3] thiazole (208 mg, 1.0 mmol) and the dry THF solution (20 ml) of 4-yl ester are successively added. -nitro-acid buffer (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] Pent-2-ene-2-carboxylate (400 mg, 1.1 mmol) at dry acetonitrile (15 ML) solution of anhydrous MgBr2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 ML) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ML) in one portion. The reaction mixture is heated to 0 ° C and stirred for 15 h at 0 ° O The mixture is diluted with ethyl acetate and washed with 5% of an aqueous solution of citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers are carried to the next stage. Pale yellow amorphous solid; Yield: 400 mg, 62%; P.F. 78 ° C; M + H 636.

Step 4: Preparation of (5R6Z) -6- (5.8-dihydro6H-imidazor2.1-b1 with 4-din-31-thiazole-2-methylmethylene) -7-oxo-4-thia-1-azabicyclo f3.2.01 acid -2-ene-2 ° carb.

Dissolve (5R) -6 - [(acetyloxy) (5,8-dihydro-6H-imidazo [2,1-b] [1,3] pyran [4,3-d] [1,3] thiazole-2 ) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid nitrobenzyl ester (500 mg, 0.79 mmol) in THF (20 ml) and acetonitrile (10 ml) ML). Freshly activated Zn powder (5.2 g) is added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred vigorously for 2 h at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 85 mg, 30%; like yellow crystals; mp 205 ° C; (M + H + Na) 383. 1 H NMR (DMSO-dβ) d 2.8 (m, 2H), 4.0 (m, 2H), 4.6 (s.2H), 6.4 (s, 1H), 6.5 (s, 1H ), 7.0 (s, 1H), 8.1 (s, 1H).

Example 16: Preparation of (5R) acid. (6Z) -6- (imidazo T2.1-b1 bebzothiazol-7-llmethyleneD ° 7 ° oxo-4-thia-1 -azabicyclo3.2.01 Pent-2-ene-2-carboxylic Step 1: Preparation of imidazof2.1-brie.3lbenzothiazol-7-ylmethanol: A solution of imidazo [2,1-b] [1,3] benzothiazole-7-carboxylic acid ethyl ester (1.1 g, 4.5 mmol) in THF ( 50 mL) is added slowly to a stirred solution of LiBH4 (1 g) in THF (100 mL) at 0 ° C. The reaction mixture is refluxed for two hours and cooled to room temperature. This is quenched with ice water and carefully neutralized with concentrated HCl. The solution is stirred at room temperature for 2 h and basified with K2CO3 (solid). At the end the reaction mixture is extracted with chloroform: methanol (3: 1) and dried over anhydrous MgSO 4. This is filtered and concentrated. The product is quite pure and is carried to the next stage without further purification. Solid coffee T.f. 75 ° C; (M + H) 205. Yield; 800 mg, (87%).

Stage 2: Preparation of 7-formyl-imidazor2.1-bip.31benzothiaz © B: The imidazo [2,1-b] [1,3] benzothiazol-7-ylmethanol (700 mg, 3.4 mmol) obtained by the above-mentioned process is oxidized with active MnO2 (2 g) in CH2Cl2 = under reflux conditions. The reaction mixture is stirred for 6 hours and cooled to room temperature. This is filtered through celite and concentrated. The separated brown solid is triturated with diethyl ether and filtered. It is found to be quite pure and carried to the next stage without purification. Performance. 400 mg (58%); (M + H) 203.

Step 3: 4-Nitrobenzyl-6-r (acetyloxy) »imidazor-2-bin, 31-benzothia / -oi 7-methyl-1-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2 -carboxylate: 7-Formyl-imidazo [2,1-b] [1,3] benzothiazole (260 mg, 1.3 mmol) and the dry THF solution (20 ml) of 4-nitro-benzyl acid ester (5R) are successively added. , 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (500 mg, 1.14 mmol) to a solution of dry acetonitrile ( mi) of anhydrous MgBr2: O (Et) 2 (390 mg, 1.5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 ml) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate and saline. . The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 450 mg, 91%; P.f. 82 ° C; M + H 630.

Step 5: (5R6Z) -6- (imidazor2.1-b1 benzothiazol-7-ylmethylene -7-oxo-4-a-1-azabicyclo-r3.2.01hept-2-ene-2-carboxylic acid: Dissolve 4-nitrobenzyl-6 - [(acetyloxy) (imidazo [2,1-b] [1,3] benzothiazol-7-yl) methyl] -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (900 mg, 1.4 mmol) in THF (20 mL) and acetonitrile (20 mL) and a 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd / C (10%) at 40 psi pressure for 6 hours. The reaction vessel is covered with film to isolate it from light. The reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is concentrated and the aqueous layer is washed with ethyl acetate. The aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 180 mg, 36%; like yellow crystals; mp 235 ° C; (M + H + Na) 378. 1 H NMR (DMSO-dβ) d 6.3 (s, 1H), 6.6 (s, 1H), 7.1 (s, 1H), 7.52 (s, 1H), 8.1-8.5 (m, 3H), 8.7 (s, 1H) ).

EXAMPLE 17 Preparation of (5R 6Z) -7-oxo-6- (f1.31 thiazolo T3.2-a1 benzamidaz @ D-2- Hmethylene) -4-thia-1-azabicyclo3.2.01hept-2-ene acid 2-carboxylic Step 1: Preparation of benzor4.51imidazof2.1-bl thiazole-2-earbaldehyde: To a solution of 2-mercaptobenzimidazole (5.0 g, 33.3 mmol) and K2CO3 (4.59 g, 33.3 mmol) in anhydrous DMF (100 ml) were added. add bromomalonaldehyde (4.99 g, 33.3) and heat for 8 hours at 80 ° C. At the end, the reaction mixture is concentrated to dryness and ice water is added and neutralized with 1N HCl. The product is extracted with chloroform and washed with water and dried over anhydrous MgSO 4. Then it is filtered and concentrated. The residue is taken as a mixture of DMF / acetic acid (1: 1) (100 ml) and heated at 120 ° C for 6 hours. The reaction mixture is concentrated and extracted with chloroform; wash well with water and dry over anhydrous MgSO 4. This is filtered and concentrated. The separated solid is triturated with diethyl ether and filtered. Yield: 4.2g (62%), (M + H) 203.

Step 2: f5R) -6-r (acetyloxy) ri, 31Tiazolor3,2-albenzimidazoyl-t) mei-IVl 3 orno 7 ^ oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2-carboxylate of 4-nitrobenzyl: Benzo [4.5] imidazo [2,1-b] thiazole-2-carbaldehyde (404 mg, 2 mmol) and the dry THF solution (20 ml) of 4-nitro-benzyl ester of acid are added successively ( 5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (772 mg, 2 mmol) to the dry acetonitrile solution (15 mg). mi) of anhydrous MgBr2: O (Et) 2 (1.65 g, excess) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 ml) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is dried for 2 h at -20 ° C and treated with acetic anhydride (1.04 ml) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° O The mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate and saline. The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to the silica gel column chromatography, then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 800 mg 63%; P.F. 78 ° C; (M + H) 630.

Step 3: acid (5R). (6Z) -7-oxo-6 (Ri.31-thiazolor-3-albenzimidazoi- 2-methylmethylene@M~tia'o 1-azabicyclo3.2.0lhept-2-ene-2-carboxylic acid: Dissolves (5R) -6 - [(acetyloxy) [1,3] thiazolo [3,2-a] benzimidazol-2-ylmethyl)] - 6-bromo-7-oxo-4-thia-1-azabicyclo [3.2 .0] 4-nitrobenzyl hept-2-ene-2-carboxylate: (630 mg, 1.0 mmol) in THF (20 mL) and acetonitrile (20 mL) dry THF (20 mL) and 0.5 M phosphate buffer (pH 6.5, 20 mL). The reaction vessel is covered with film to isolate it from light. The reaction mixture is filtered, cooled to 3 ° C, and 1N NaOH is added to adjust the pH to 8.5. The filtrate is concentrated and the aqueous layer is washed with ethyl acetate. The aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by HP21 reverse phase column chromatography of resin. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 190 mg 50%; as yellow crystals p.f. 240 ° C (Dec); (M + H + Na) 378. 1 H NMR (DMSO-dβ) d 6.3 (s, 1H), 6.4 3 (s, 1H), 6.6 (d, 2H), 7.29-7.39 (m, 2H), 7.69-7.73 (t, 1H), 8.1- 8.19 (m, 1H) 8.84 (s, 1H).

Example 18 Preparation of (5R) acid. (6Z) -6-t7.8-dihydro-6H-cyclopentant3.4lpirazotoi§.1 ° bip.31-thiazol-2-yl methylene) -7-oxo-6-4-thia-1-azabicyclo3.2.01hept-2- eno ° 2-caríb > Oxylic: Stage 1: Preparation of 7.9-dihydro-6H-cyclopenta3.41-pyrazole-5,1-bip.31-azole-2-carbaldehyde: To a stirred solution of 1,4,5,6-tetrahydrocyclopenta [c] pyrazole-3 (H) -thione [prepared by the procedure of T. takeshima, N. Oskada, E. Okabe and F. mneshima, J. Chem Soc. Perkin. Trans. I, 1277-1279, (1975)] (5.3 g, 37.85 mmol) and K2CO3 (10.4 g, 75 mmol) in anhydrous DMF (100 mL) is added bromomalonaldehyde (5.7 g, 37.85) and heated for 8 hours to 80 C. At the end, the reaction mixture is concentrated to dryness and ice water is added and neutralized with 1N HCl. The product is extracted with chloroform and washed with water and dried over anhydrous MgSO. This is filtered and concentrated. The residue is taken up in a mixture of DMF / acetic acid (1: 1) (100 mL) and heated at 120 ° C for 6 hours. The reaction mixture is concentrated and extracted with chloroform; wash well with water and dry over anhydrous MgSO. This is filtered and concentrated. The product is purified by SiO2 column chromatography by elution with 75% ethyl acetate: hexane. Yield: 2.2 g (30%) P.F. 112 ° C; (M + H) 193.

Step 2: 4-Nitrobenzyl- (5R) -6-f (acetyloxy) (7.8-dihydro-8H-cyclopentant.3.41-pyrazototo-5,1l-b1H.31-thiazol-2-yl-methy-6-bromo-7-oxo-4-thia -1-azabicyclo3.2.01hept-2-ene-2 ° carboxylate 7.9-Dihydro-6H-cyclopenta [3,4] pyrazolo [5,1-b] [1,3-thiazole-2-carbaldehyde (576 mg, 3 mmol) and the dry THF solution (20 mL) are successively added. of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (1.16g, 3 mmol) ) to the solution of dry acetonitrile (15 mL) of anhydrous MgBr 2: O (Et) 2 (1.65 g, excess) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 mL) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° O the mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 1.5 g, 83%; P.F. 69 ° C; (M + H) 620.

Step 3: (5R 6Z) 6- (7.8-Dihydro-6H-cyclopentant3.41-pyrazolar-5-bin.3-nazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2 acid -eno-2-carboxylic acid: Dissolve 4-nitrobenzyl- (5R) 6 - [(acetyloxy) (7,8-dihydro-8H-cyclopenta [3,4] pyrazolo [5,1-b] [1,3] thiazol-2-ylmethyl] -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (1.2 g, 1.9 mmol) in THF (30 mL) and acetonitrile (30 mL) and a 0.5 M phosphate buffer (pH 6.5, 30 mL) and hydrogenated over Pd / C (10%) at 40 psi pressure for 6 hours.The reaction vessel is covered with foil to isolate it from the light. The reaction medium is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5.The filtrate is concentrated and the aqueous layer is washed with ethyl acetate.The aqueous layer is separated.The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water The fractions containing the product are collected and concentrated under reduced pressure gone at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 420 mg, 38%; like yellow crystals; mp 190 ° C; (M + H + Na) 368. 1 H NMR (DMSO-dβ) 1 H NMR (DMSO-d 6) d 2.38-2.42 (m, 2 H), 2.69-2.89 (m, 4 H), 6.57 (s, 1 H), 6.58 (s, 1 H), 7.36 (s) , 1H), 8.53 (s, 1H).

Example 19 Preparation of (5R6Z) -7-oxo-6- (5.6.7.8-tetrahydroimidazor2 ° blf 1.31methiazol-2-ylmethylene) -4-thia-1-azabicyclo3.2.01hept-2-ene-2- acid carbo; cico: Stage 1: Preparation of 5.6.7.8- tetrahydroimidazor2.1-biri.31benzothiazo8 ° 2 ° ethyl carboxylate A mixture of 2-chlorocycloexanone (13.2 gm, 100 mmol) and thiourea (8.0 g 101 mmol) is refluxed in ethanol: THF (1: 2) for 16 hours. The reaction mixture is cooled to room temperature and the separated white solid is filtered. (12.0 g separated) This is dissolved in anhydrous ethanol (100 mL) and sodium methoxide (3.3 g, 63 mmol). To this is added ethyl bromopyrulate (15.0 g) and stirred at room temperature for 2 hours. Then it refluxes for 48 hours. At the end the reaction mixture is cooled to room temperature and concentrated. The residue is extracted with chloroform and washed well with water. The product is purified by silica gel column chromatography by eluting with 50% ethyl acetate: hexane. Semi solid red; Yield: 6.2 g (39%); M + H 251.

The ester is reduced with LiBH and the resulting alcohol is oxidized with active MnO2. The aldehyde obtained is taken to the next stage.

Step 3: Preparation of (5R) -6 (acetyloxy) - (5.6.8-tetrahydrort) idazo ['2 1 -bip.31-benzothiazol-2-ylmethyl) 1-6-bromo-7-oxo-4- thia-1-azabicyclo3.2.01hept-2 ° e? p? o ° 2 ° carboxylate of 4-nitrobenzyl.

Sucrose, 5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benthioiazole-2-carbaldehyde (412 mg, 2.0 mmol) and the dry THF solution 820 mL) are added in succession. 4-Nitrobenzyl (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (770 mg, 2 mmol) at dry acetonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (1 2g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with film to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 980 mg, 77%; M + H 634.

Stage 4: Preparation of acid. (5R 6Z) -7-oxo-6- (5.6.7.8-tetrahydrodimidazoyl) -2.fl.blH. 31 benzo thiazol-2-yl methylene) -4-thia-1-azabicyclo3.2.01hept-2-ene-2- carboxy85eo: It is dissolved (5R) -6 - [(acetyloxy) (5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-ylmethyl) -6-bromo-7-oxo- 4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl. (980 mg, 1.57 mmol) in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn powder (5.2g) with 0.5M phosphate buffer (pH 6.5, 28 mL) is added rapidly. The reaction vessel is covered with foil to isolate it from light. The reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate. The aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 120 mg, 20%; like yellow crystals; mp 250 ° C; (Dec) (M + H + Na) 382. 1 H NMR (DMSO-d 6) d 1.9 (m, 2 H), 2.5 (m, 2 H), 3.2-3.4 (m, 4 H), 6.6 (m, 1 H) , 7.1 (s, 1H), 7.5 (s, 1H), 8.1 (s, 1H).

Example 20 Preparation of (5R) acid. (6Z) -8- (9-methyl-9H-imidazon.2-albenzimidaz@l°2° ilmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2-earboxyl Step 1: Preparation of 9-methyl-9H-8-midazori.2-a1beneimidazole-2"Carbaldß [hório.

To a stirred solution of LiBH4 (1.79 g, 82 mmol) in THF at 0 ° C is added dropwise 9-methyl-9H-imidazo [1, 2-a] benzimidazole-2-carboxylic acid ethyl ester (2.5 g, 10.3 mmol). The reaction mixture is refluxed for two hours, and cooled to room temperature. The Ti is carefully quenched with ice water and acidified with concentrated HCl to pH 4. The reaction mixture is stirred at room temperature for one hour and basified with K2CO3. The residue is extracted with chloroform; methanol (3: 1) and dried over anhydrous MgSO. This is filtered and concentrated. Yield: 1.3 g, (65%). (M + H) 202.

The residue (1.3g, 6.4 mmol) is oxidized with MnO2 (5.0 g) in CH2Cl2 under reflux conditions. After it is finished, the reaction mixture is filtered and concentrated. This is purified by column chromatography on SiO2 by eluting with 1: 1 ethyl acetate: hexane. Solid coffee Production 330 mg, (25%); (M + H) 200.

Step 2: Preparation of (5R) -6-r (acetyloxy) - (9-methyl-9H-imidazort-2-a1benzylamine (dlazoll) 2-metip-6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01 4-nitrobenzyl hept-2-ene-2-carboxylate: 9-Methyl-9H-imidazo [1,2-a] benzimidazole-2-carbaldehyde (330 mg, 1.65 mmol) and the dry THF solution (20 mL) of 4-nitro-benzyl acid ester (5R, 6S) are successively added. ) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (770 mg, 2 mmol) to the solution of dry acetonitrile (15 mL) of MgBr2 anhydrous: O (Et) 2 (1.2g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° O the mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the diastereomer mixture is brought to the next stage. Pale yellow amorphous solid; Yield: 330 mg, 31%; (M + H) Step 3: Preparation of acid (5R). (6Z) -8- (9-methyl-9H-imidazof1.2-albenzyltriidazole-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2-carboxylic acid. (5R) -6 - [(acetyloxy) - (9-methyl-9H-imidazo [1, 2-a] benzimidazol-2-methyl] -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2 .0] hept-2-ene-2-carboxylate of 4-nitrobenzyl: Dissolve (1 g, 1.6 mmol) in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn powder (5.2g) is added quickly with a 0.5M phosphate buffer (pH 6.5, 28 mL). The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred vigorously for 2 hours at room temperature. The reaction mixture is filtered, cooled to 3 ° C, and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate. The aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 140 mg, 23%; like yellow crystals; mp 220 ° C; (Dec) (M + H + Na) 375. 1 H NMR (DMSO-d 6) d 3.4 (s, 3 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 7.01 (s, 1 H), 7.21 ( t, 1H), 7.3 (t, 1H), 7.56 (d, 1H), 7.85 (d, 1H, 8.1 (s, 1H).

Example 21 Preparation of (5R.6Z) -7-oxo-6- (4H-thienor2'3 ': 4.51 thiopi? Anor2.3-blp i: lin 2 illmethylene) -4-thia-1-azabiclor3.2.01hept acid -2-ene-2-carboxylic acid (sodium salt Stage 1: 2.3-dihydro-4H-thiopyranof2,3-b1pyridin-4-one: A solution of 14 g. (61.6 mmol) of 3- (3-carboxy-2-pyridylthio) propionic acid [as described in the literature: J. Heterocvclic Chem. 37.379 (2000) 1 and 15 g (185 mmol, 3 equivalents) of ethyl acetate. Anhydrous sodium, 200 ml of acetic anhydride is refluxed (160 ° C) under agitation, N2 atmosphere? dry conditions, for 2 hours. It is cooled, diluted with 300 ml of water, basified with a 30% solution of ammonium hydroxide to a pH of 8-9, extracted with 3 × 200 ml of chloroform. The combined organics are washed with 2x60 ml of sodium bicarbonate (saturated solution), water, dried, evaporated, gives 2.8 g (27%) of the title compound, reddish solid, P.F. 66-8 ° C, (M + H) + = 166.2.

Stage 2: 4-chloro-2H-thiopyranof2,3b-pyridine-3-carbaldehydes: A solution of 6.6 g (43 mmol, 1 equivalent) of phosphorous oxychloride in 30 ml of methylene chloride is added dropwise to 3.95 g (43 mmol, 1.25 equivalents) of anhydrous dimethylformamide (0 ° C stirring, N 2 atmosphere, dry conditions) with such a proportion to maintain the temperature between 0 to 5 ° C; the reaction mixture is stirred at RT for 2 hours, cooled to 0 ° C, and a solution of 8.9 g (54 mmol, 1.25 equivalents) of 2,3-dihydro-4H-thiopyran is added dropwise [2.3 b) pyridin-4-one in 30 ml of methylene chloride over a period of 20 minutes. The MR is stirred at room temperature for 2 hours, poured onto crushed ice: mixture of: ethyl acetate 4: 1, extracted with 4 x 150 ml of methylene chloride, the combined organics are washed with water, dried, evaporate and give 7.76 g (68%) of the title compound, brown solid, mp 56-8 ° C, (M + H) + = 212.6.

Step 3: 4H-Thienor2'3 ': 4,51-thiopyranor 2,3-b-pyridine-2-carboxylic acid ethyl ester: To a solution of 7.5 g (35 mmol, 1 equivalent) of 4-chloro-2H-thiopyrano [2,3-b] pyridine-3-carbaldehyde in 250 ml of methylene chloride are added (under stirring, N 2 atmosphere, dry conditions): 4.7 g (39 mmol, 1.1 equivalents) of mercapto ethyl acetate, and 7.2 g (71 mmol, 2 equivalents) of triethylamine in 30 ml of methylene chloride. The reaction mixture is refluxed for 2 hours, quenched with 100 ml of water, the organics are separated, the water is extracted with 4 × 150 ml of methylene chloride, the combined organics are dried and evaporated. The residue is purified on a column of silica gel, using hexane: ethyl acetate 3: 1 as a solvent, gives 7.6 g (78%) of the title compound, yellow crystals, P.F. 113-5 ° C, (M + H) + = 278.3.

Step 4: 4H-Thienor2'3 ': 4.51-thio-pyranoyl-2,3-b1-pyridin-2-methane: To a cold solution of 7.5 g (37 mmol) of ethyl 4H-thieno- [2'3 ': 4,5] thiopyrano [2,3-b] pyridine-2-carboxylate in 300 ml of dry tetrahydrofuran (0). ° C, N2 atmosphere, dry condition) 60 ml (60 mmol, 2.1 equivalents) of a cold 1 M solution of lithium aluminum hydride in tetrahydroflurane are added dropwise, and the MR is stirred at RT until the MS disappears (monitored by TLC / MS). It is cooled to 0 ° C, the MR is quenched with an aqueous 2 N formic acid solution to neutralize at pH = 8, and it is stirred at RT for 2 hours, filtered, the filtrate is extracted with 4 × 200 ml of sodium chloride. methylene, the combined organics are dried, evaporated to give 6.0 g (94%) of the title compound, yellow crystals, mp 112-4 ° C, (M + H) + = 236.4.

Ecapa 5: 4H-t-inol2,3 ': 4,51-thiopyrin-2,3-blpiridin-2-carbaidehyd: To a solution of 3.0 g (12.8 mmol) of 4H-thieno [2'3 ': 4,5] thiopyrano [2,3-b] pyridin-2-ylmethanol in 200 ml of chloroform, 9.0 g (80 mmol. , 7 equivalents) of activated manganese (IV) oxide, and the MR is refluxed under stirring, N2 atmosphere, for 12 hours. It is filtered through a pad of celite, the filtrate is evaporated and the residue purified on a column of silica gel, gives 2.5 g (86%) of the title compound, yellow crystals, m.p. 93-5 ° C, (M + H) + = 234.4.

Step 6: (5R) -6-r (acetyloxy) (4H-thieno, 2'3 ': 4.51 thiopyranor2.3-blpiridin-2-yl) rneu 1-6 ° bromo-7-oxo-4-thia-1 -zabicyclo3.2.01hept-2-ene-2-carboxylate of 4-nitrobere lo: In a sealed dry round bottom flask, rinsed with N2, add: 4H-thieno [2'3 ': 4,5] thiopyrano [2,3-b] pyridin-2-carbaldehyde 0.6 g (2.57 mmol, 1 equivalent) ), to anhydrous THF (15 mL), anhydrous ACN (15 mL) 0.520 g (2.8 mmol, 1.1 equivalents) of anhydrous MgBr2, and the reaction mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added 2.5 ml (14 mmol, 5 equivalents) of anhydrous triethylamine, 10 ml of anhydrous THF, the reaction mixture is cooled to (-20 ° C), and 0.95 g (2.5 mmol, 1) is added. equivalent) of bromopenam. The MR is stirred at (-20 ° C) for 6 hours. At the same temperature, add 3 ml (3 mmol, 1.15 equivalents) of acetic anhydride, the MR is stirred for 15 minutes and kept at 0 ° C for 12 hours, evaporated to dryness, the residue is extracted with 5x80 ml. of ethyl acetate. The organic solvent is evaporated, and the residue purified on a column of silica gel (hexane solvent: ethyl acetate 4: 1), gives 0.880 g (52%) of the title compound, yellow crystals, m.p. 141-3 ° C, (M + H) + = 661.6.

Step 7: (5R.6Z) -7-oxo-6- (4H-thien2'3 ': 4,51 thiopyranor2.3-bloteridin-2 ° 8l) methylene 1-4-thia-1-azabicyclo3.2.01 acid Hept-2-ene-2-carboxylic acid (sodium salt).

A solution of (5R) -6 - [(acetyloxy) (4H-thieno [2'3 ': 4,5] thiopyrano [2,3-b] pyridin-2-yl) methyl] -6-bromo-7- oxo-4-thia-1-azabicyclo [3.2.0] hept-ene-2-carboxylate of 4-nitrobenzyl: 0.8 g (1.21 mmol, 1 quivalent) in 40 ml of THF and 40 ml of a phosphate buffer ( pH = 6.36) is hydrogenated at 40 psi for 3 hours in the presence of 0.4 g 10% palladium on carbon catalyst. The reaction mixture is filtered through a pad of celite, filtered and adjusted to pH = 8.0, concentrated in vacuo, the residue purified on a reverse phase column (amberlifa), using 5% to 10% of a ACN / water mixture as solvent, gives 0.103 g (21%) of the title compound, reddish crystals, mp 362.4 ° C, (M + H) + = 409.5. 1 H NMR (DMSO-d 6) d 4.12 (s, 2 H), 6.49 (s, 1 H), 6.53 (s, 1 H), 7.22 (d, 1 H), 7.34 (s, 1 H), 7.41 9 s, 1 H ), 7.76 (t, 1 H) "8.28 (d, 1 H).

EXAMPLE 22 Preparation of sodium salt, acid (5R, 6Z) -6-i (5-methyl-? D dihydro-fcir cyclopentareiri.2.41triazolofl.5-alpyrimidin-2-yl) methylene) -7 ° oxo-4- tia ° 1] - azabicyclo3.2.01hept-2-ene-2-carboxylic acid: STAGE 1: PREPARATION OF (8-METHYL-6.7-DIHYDRO-5H-CICLOPENTARDip .2.41 TRIAZOLOI1.5- 1 PYRIMIDIN-2-IDMETANOL In a round bottom flask, 3.78 grams of 2-acetylcyclopentanone, 3.52 grams of (5-amino-1 H- [1,4] triazol-3-yl) -methanol and 50 ml of 2-methoxyethanol are charged. The mixture is refluxed for 18 hours. It is then cooled to 23 ° C and concentrated to 5 ml. then 50 ml of ethyl ether are added and the precipitate is filtered and dried under vacuum to yield 2.0 grams of the product. This compound is used directly in the next stage. MS: 205.2 (M + H). H NMR (DMSO) d 5.55 (t, 1H, OH, J = 6.2 Hz), 4.63 (d, 2H, J = 6.2 Hz), 3.28 (m, 2H), 3.02 (t, 2H, CH2, J = 6.8 Hz), 2.51 (s, 3H.CH3), 2.27 (m, 2H, CH2).

Stage 2: Preparation of 8-methyl-6.7- dihydro-5H-cyclopentadir.2.21triaz@l i Alpyrimidine-2-carbaldehyde 0.17 ml of DMSO and 1 ml of dichloromethane are charged in a round bottom flask. The mixture is cooled to -50 ~ -60 ° O Then a mixture of 0.1 ml of oxalyl chloride and 2 ml of dichloromethane is injected into the bottle all at once. The mixture is stirred at the same temperature for another 5 minutes. Then 0.174 grams of (8-methyl-6,7-dihydro-5H-cyclopenta [d] [1,2,4] triazole [1, 5-a] pyrimidin-2-yl) methanol in 2 ml of dichloromethane is added. in a period of 2 minutes. The mixture is stirred at -50-60 ° C for fifteen minutes and 0.7 ml of triethylamine is added immediately. After a further five minutes the reaction medium is heated to 23 ° C and a mixture of 20 ml of water and 200 ml of dichloromethane is added. The organic layer is dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated yielding 0.153 grams of the product (89%). MS: 203.1 (M + H). H-NMR (CDCl 3): d 10.24 (s, 1 H), 3.49 (m, 2 H), 3.15 (m, 2 H), 2.67 (s, 3 H, CH 3), 2.44 (m, 2 H.CH 2).

Step 3: Preparation of (5Rl-6-r (acetyloxy) -7,8-dihydro-6H cielopentardip .2.41triazoloH, 5-a1pyrimidin-2-yl) metill-6-bromo-7-oxo-4-ftia-1] - azabiciclof3.2.01hept-2-ene-2-carboxylate 4-nitrobenzyl Successively add 8-methyl-6,7-dihydro-5H-cyclopenta [e] [1,2,4] triazolo [1,5-a] pyrimidine-2-carbaldehyde (153 mg, 0.75 mmol) and dry THF solution (20 mL) of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (20 mL) 385 mg, 1 mmol) was added to the dry acetatonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 200 mg, 42%; (M + H) 631.

Step 4: Preparation of (5R.6z) -6-r (5-methyl-7.8-dihydro-6H-cyclopentafeiri .2.41triazolop .5-alpyrimidin-2-yl) methylene) -7-oxo-4-thiazide acid 1-azabicyclo3.2.01hept-2-ene-2-carboxylic acid: It dissolves (5r) -6 - [(acetyloxy) - (5-methyl-7,8-dihydro-6H-cyclopenta [e] [1, 2,4] triezolo [1, 5-a] pyrimidin-2-yl) ) methyl-6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl. (200 mg, 0.31 mmol) f in THF (20 mL) and acetonitrile (20 mL) and a phosphate buffer (pH 6.5) (20 mL) and hydrogenated over Pd / C (10%) (200 mg) to 40 pressure psi. At the end, the reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 I) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 15 mg, 13%; like yellow crystals; mp 250 ° C; (Dec); (M + H + Na) 378. 1 hrmn (dmso-d6) d 6.80 (s, 1H), 6.76 (s, 1H), 6.25 (s, 1H), 3.24 (m, 2H), 2.96 (m, 2H) ), 2.49 (s, 3H), 2.25 (m, 2H).

EXAMPLE 23 Preparation of sodium salt, acid (5R.6Z) -6-r (ethoxycarbonyl) -6 .8.S) ° tetrahydropyridof3.4-eiri .2.41triazoloH, 5-a1pyrimidin-2-yl) methyl)) - 7-oxo-4 ° tña ° H ° azabiciclor3.2.01hept-2-ene-2-carboxylic STAGE 1: PREPARATION OF ACID ETHYL STYLE 2-HYDROXYMETHYL-8.9-DIHYDRO-6H-1.3.4.7.9B-PENTMZA-CICLOPENTAGA1NAPFTALENO-7-CARBOXÍLICO To a round bottom flask is charged 8.56 grams of 4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture is refluxed at 90 ° C for 2 hours. It is then poured into 75 ml of water and extracted with 2 x 250 ml of dichloromethane. The combined organic layers are washed with 50 ml of saline and dried over magnesium sulfate. The drying agent is filtered and the concentrate gives 28 grams of ethyl ester of 3-dimethylaminomethylene-4-oxo-pyridine-1-carboxylic acid. This material (12.8 grams) then to a round bottom flask is charged together with 3.42 (5-amino-1 H- [1,2,4] triazol-3-yl) -methanol and 100 ml of 2-methoxyethanol . The mixture is refluxed for 18 hours. It is then cooled to 23 ° C and concentrated to 5 ml. Then 50 ml of ethyl ether is added and the precipitate is filtered and dried in vacuo to yield 1.5 grams of the product. MS: 278.1 (M + H). H NMR (CDCl 3): d 8.60 (S, 1H), 4.98 (s, 2H), 4.78 (s, 2H, CH2), 4.22 (q, 2H, J = 4.8 Hz), 3.75 (t, 2H.CH2, J = 4 Hz), 3.51 (t, 2H, J = 4 Hz), 1.32 (m, 3H, CH3, J = 4.8Hz).

Step 2: Preparation of ethyl ester of 2-formyl-8.9-diihi-lH-1,3.4.7.9b-pentaaza-iclopentara-naphthalene-7-carboxylic acid: Ethyl ester of 2-hydroxymethyl-8,9-dihydro-6H-1, 3,4,7,9b-pentaaza-iclopenta [a] naphthalene-7-carboxylic acid (861 mg, 3 mmol) is converted to Ethyl 2-formyl-8,9-dihydro-6H-1, 3,4,7,9b-pentaaza-iclopenta [a] naphthalene-7-carboxylic acid (690 mg, 89% yield) by the procedure outlined in Example 22, (step 2).

MS: 276.1 (M + H). H NMR (CDCl 3): d 10.24 (s, 1 H), 8.76, (s, 1H), 4.86 (s, 2H), 4.23 (q, 2H, CH2, J = 7.2 Hz), 4.13 (t, 2H, CH2, J = 7.2 Hz), 3.39 (t, 2H, CH2, J = 5.7 Hz), 1.34 (m, 3H, CH3, J = 7.2 Hz).

Step 3: 2-f (acetyloxy) ((5R) -6-bromo-2- (r4-nitrobenzyl) oxcarbonyl> -7 ° 8o-4 thia-1-azabicyclo3.2.01hept-2-en-1 ) metill-8.9-dihydropyridof3.4-eip .2.41 triazolyl) 5 l pyrimidine-7- (6 / V) -ethylcarboxylate Ethyl ester of 2-formyl-8,9-dihydro-6H-1, 3,4,7,9b-pentaaza-cyclopenta [a] naphthalene-7-carboxylic acid (550 mg, 2 mmol) is successively added and the dry THF solution (20 mL) of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-4-nitrobenzyl ester 2-carboxylic acid (770 mg, 2 mmol) to the dry acetonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 220 mg, 15%; (M + H) 703.

Step 4: Preparation of (5R.6Z) -6 - ((r7- (ethoxycarboniCl) -i.7.8.9-tetrahydropyrid3.4-e1-ri.2.41triazolo-f1.5-alpyrimidin-2 acid -nmethylene ^ -7-oxo-4 35 ° 1l-azabiciclof3.2.01hept-2-ene-2-carboxylic Dissolve 2 - [(acetyloxy) ((5R) -6-bromo-2- { [4-nitrobenzyl) oxy] carbonyl} -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-6-yl) methyl] -8,9-dihydropyrido [3,4-e] [1, 2,4] triazolo [1 , 5-a] pyrimidine-7- (6H) -ethyl carboxylate (220 mg, 0.28 mmol) in THF (20 mL) and acetatonitrile (20 mL) and a phosphate buffer (pH 6.5) (20 mL) and hydrogenate over Pd / C (10%) (200 mg) at 40 psi pressure. At the end, the reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin. Initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 15 mg, 2%; like yellow crystals; pf > 250 ° C; (Dec); (M + H + Na) 449. 1 H NMR (DMSO-d 6) d 8.61 (s, 1 H), 7.01 (s, 1 H), 6.90 (s, 1 H), 6.44 (s, 1 H), 4.74 (m, 2H, CH2), 4.13 (q, 2H, J = 5.4 Hz), 3.84 (s, m, 2H.CH2), 1.22 (t, 3H, CH3, J = 5.7 Hz).

EXAMPLE 24 Preparation of sodium salt, acid (5R.6Z) -6- (8'9'-dihydrate- Respiro: dioxolane-2.7'-ri.2.41triazolo-ri.5-a1quinazolin1-2'-ilmethylene) -7 -oxo-4-thia-H-azabicic8or3.2.01hept-2-ene-2-carboxylic STAGE 1: PREPARATION OF 2-HYDROXYMETHYL-CETAL-8.9-DIHYDRO-6H-f 1.2.41 TRIAZOLO-M .5-A1QUINAZOLIN1-7 -ETHYLENE In a round bottom flask are charged 15.6 grams of 1,4-cycloexalione mono-ethylene ketal, 11.9 g of dimethylformamide dimethylacetal, the mixture is refluxed at 90 ° C for 2 hours. It is then poured into 75 ml of water and extracted with 2 x 250 ml of dichloromethane. The combined organic layers are washed with 50 ml of saline and dried over magnesium sulfate. The drying agent is filtered and the concentrate gives 28 grams of 3-dimethylaminomethylene-4-oxo-cyclohexane. The crude product then to a round bottom flask is charged together with 11.9 grams of (5-amino-1H- [1,2,4] triazol-3-yl) -methanol and 100 ml of 2-methoxyethanol. The mixture is refluxed for 18 hours. It is then cooled to 23 ° C and concentrated to 5 ml. then 50 ml of ethyl ether is added and the precipitate is filtered and dried under vacuum to yield 2.0 grams (8% of the product). MS: 263 (M + H). H NMR (CDCl 3): d 8.51 (s, 1 H), 5.17 (s, 2 H, CH 2), 4.08 (s, 4 H, OCH 2 CH 2 O), 3.42 (t, 2 H, CH 2, J = 5.1 Hz), 3.07 (s 2 H .CH2), 2.15 (t, 3H, CH3, J = 5.1 Hz).

Stage 2: Preparation of 7-ethyleneketal-6.7.8.9-tetrahydro-r 2.41triazo8o H.5 ° alquinazoline-2-carbaldehyde In a round-bottomed flask, 5 ml of dmso is charged, the mixture is cooled to -50-60 ° C. Then a mixture of 1 ml of oxalyl chloride and 5 ml of dichloromotan is injected into the bottle at once. The mixture is stirred at the same temperature for another five minutes. Then ketal of 2-hydroxymethyl-8,9-dihydro-6H -] [1,2,4] triazole [1, 5-a] quinazolin-7-ethylene (1.31 g, 5 mmol) in 20 ml of dichloromethane is added. in a period of 2 minutes. The mixture is stirred at -50 ~ -60 ° O for 15 minutes and 0.7 ml of triethylamine is added immediately. After a further five minutes the reaction medium is heated to 23 ° C and a mixture of 20 ml of water and 200 ml of dichloromethane is added. The organic layer is dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated yielding 910 mg of the product (70%). Ms: 261 (m + h). H NMR (CDCl 3): d 10.26 (s, 1H), 8.66 (s, 1H), 4.08 (s, 4H, och2ch2o), 3.49 (t, 2H, j = 6.9 hz), 3.11 (s, 2H), 2.18 (t, 3H, CH3, J = 6.9 Hz), 2.44 (m, 2H, CH2).

Step 3: Preparation of (5R) -6-r (acetyloxy) -8'.9'-dihydro-6'H-espirori.3-dio? IS) lg? No ° 2.7'-f 1.2.41triazoloH .5- a1quinazolin1-2'-ii) methyl) 6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept-2-ene-2-carboxylate of 4-nitrobenzyl. 7-Ethylene-acetal-6,7,8,9-tetrahydro- [1,2,4] triazolo [1,5-a] quinazolin] -2-carbaldehyde (780 mg, 3 mmol) and the THF solution are successively added. dry (20 mL) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.15 g, 3 mmol) was added to the dry acetonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3 N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 300 mg, 15%; (M + H) 688.8.

Step 4: Preparation of acid (5R.6Z) -6- (8,9, -dihydro-6? -spiro-n.3-d¡oxoBapo ° 2, ° n .2.41triazolo-p, 5-a1ainazolin1-2 '-methylene) -7-oxo-4-thia-1-azabicyclo3.2.01B? ®pt-2-ene-2-carboxylic acid Dissolve (5R, 6Z) -6 - ([(acetyloxy) -8'.9'-dihydro-6? -spiro [1, 3-dioxolane-2,7'- [1,2,4] triazolo [1, 5-a] quinazolin] -2'-yl) methyl) -6-bromo-7-oxo-4-thia-1- azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (300 mg.0.43 mmol) in THF (20 mL) and acetonitrile (20 mL) and a phosphate buffer (pH 6.5) (20 mL) ) and hydrogenated over Pd / C (10%) (200 mg) at 40 psi pressure. At the end, the reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 15 mg, 9%; yellow crystals; pf > 250 ° C; (Dec); (M + H + Na) 435.9. 1 H NMR (DMSO-d 6) d 8.50 (s, 1 H), 6.97 (s, 1 H), 6.85 (s, 1 H), 6.38 (s, 1 H), 4.05 (s, 4 H, OCH 2 CH 2 O), 3.28 (s) m, 2H), 3.07 (s, 2H), 2.13 (t, 3H, CH3, J = 4.8 Hz).

EXAMPLE 25 Preparation of sodium salt, (5R.6Z) -6-r (5-methy8-8.7.8.9-tetrahydroH2.21triazolop.5-a1quinazolin-2-yl) methylene) - 7-oxo-4- acid thia 1l - azabicyclo3.2.01hept-2-ene-2-carboxylic acid STAGE 1: PREPARATION OF (5-METHYL-6.7.8.9-TETRAHYDROM .2.41 TRIAZOL? Ri. 5-1QUINAZOLIN-2-IDMETANOL: In a round-bottomed flask are charged 4.2 grams of 2-acetylcyclohexanone, 3.52 grams of (5-amino-1 H- [1,2,4] triazol-3-yl) -methanol and 50 ml of 2-methoxyethanol. The mixture is refluxed for 18 hours. It is then cooled to 23 ° C and concentrated to 5 μm. then 50 ml of ethyl ether are added and the precipitate is filtered and dried under vacuum to yield 3.32 grams of product. Yield 49%. This compound is used directly in the next stage. MS: 219.2 (M + H). H NMR (DMSO) d 5.49 (t, 1 H, OH, J = 6 Hz), 4.61 (d, 2H, J = 6Hz), 3.24 (m, 2H), 2.93 (m, 2H), 2.69 (s, 3H), 2.52 (s, 2H), 1.84 (m, 4H).

Stage 2: Preparation of 5-methyl-6.7.8.9-tetrahydron.2.41triazolof 5-a1quinazollñn-2 ° carbaldehyde To a round bottom flask is charged with 1 ml of DMSO and 5 ml of dichloromethane. The mixture is cooled between -50 ~ -60 ° C. Then a mixture of 1 ml of oleyl chloride and 2 ml of dichloromethane is injected into the bottle at once. The mixture is stirred at the same temperature for another 5 minutes. Then 0.218 grams of (5-methyl-6,7,8,9-tetrahydro [1,4] triazolo [1,5-a] quinazolin-2-yl) -methanol in 2 ml of dichloromethane is added in a 2 minute period. The mixture is stirred at -50-60 ° C for 15 minutes and 0.7 ml of triethylamine is added immediately. After a further five minutes the reaction medium is heated to 23 ° C and a mixture of 20 ml of water and 200 ml of dichloromethane is added. The organic layer is dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated yielding 0.216 grams of the product (99%). MS: 217 (M + H). H NMR (CDCl 3): d 10.20 (s, 1 H), 3.23 (m, 2 H), 2.78 (m, 2 H), 2.63 (s, 3 H, CH 3), 2.00 (m, 4 H).

Step 3: Preparation of (5R) -6-r (acetylox8H5-Methyl-6.7.8.S ° tetrahydroH .2.41triazoloH .5-a1quinazolin-2-yl) -methyl) -6-bromo-7-oxo-4- tBa-1 ° azabicyclo3.2.01hept-2-ene-2-carboxylate of 4-nitrobenzyl Successively add 5-Methyl-6,7,8,9-tetrahydro [1, 2,4] triazolo [1,5-a] quinazoline-carbaldehyde (432 mg, 2 mmol) and the dry THF solution (20 mL ) of 4-nitro-benzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (170 mg, 2 mmol) was added to the dry acetonitrile solution (15 mL) of anhydrous MgBr2: O (Et) 2 (1.2 g, 3.0 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereomers is carried to the next stage. Pale yellow amorphous solid; Yield: 600 mg, 47%; (M + H) 644.7.

Step 4: Preparation of (5R.6Z) -6-r (5-methyl-6.7.8.9-tetrahydrole.2.41triazoloH.5-a1quinazolin-2-yl) methylene) - 7-oxo-4 a-1 acid azabicyclo3.2.01hept-2-ene-2-carboxylic acid.

Dissolve (5R) -6 - [(acetyloxy) - (5-Methyl-6,7,8,9-tetrahydro [1, 2,4] triazolo [1, 5-a] quinazolin-2-yl) -methyl ) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl. (600 mg, 0.93 mmol) in THF (20 mL) and acetonitrile (20 mL) and a phosphate buffer (pH 6.5) (20 mL) and hydrogenated over Pd / C (10%) (200 mg) at 40 psi of pressure. At the end, the reaction mixture is filtered, cooled to 3 ° C and 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone, filtered and dried. Yield: 37 mg, 11%; like yellow crystals; mp 250 ° C; (Dec); (M + H + Na) 392. 1 H NMR (DMSO-d 6) d 6.90 (s, 1 H), 6.85 (s, 1 H), 6.28 (s, 1 H), 2.98 (m, 2 H), 2.77 (m, 2 H) ), 2.55 (m, 3H), 1.78 (m, 4H).

EXAMPLE 26 Preparation of sodium salt, acid (5R.6Z) -6-r (5-methoxy-7"8 ° dihydro @ H ° cyclopentare1imidazon.2-a1-pyrimidin-2-yl) methylene) -7-oxo-4 -thia-1 ° azabicyclo3.2.01hept-2-ene-2-carboxylic acid: STEP 1: PREPARATION OF 4-METOXY-6.7-DIHYDRO-5H-CICLOPENTAPIRIIVUDIN-2-ILAMINE (SM: Ross, L., Goodman, L., Baker, B.R.A. Am. Chem. Soc. 1959, 81, 3108). 5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine are dissolved in 200 ml of xylene and 30 ml of absolute methanol. Then 5.4 grams is added for sodium methoxide and the mixture is refluxed for 3 hours. Then the solvent is removed in vacuo and 100 ml of water is added to the residue. Filter and wash the cake with water (50 mL). The solid is placed under vacuum additionally for drying for several hours. The desired product weighs 4.8 g (98% yield). P.f .: 133.8 ~ 134.9 ° C; MS: 166.2.0 (M + H).

Step 2: Preparation of 5-methoxy-7,8-dihydro-6H-3,4,8-triaza-as-indacene-2-carboxylic acid ethyl ester. 4.8 grams (19.8 mmol) of 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine are dissolved in 100 ml of dry THF. Then bromopyruvate (5.4 mL) is added dropwise in a period of 5 minutes. The mixture is stirred at 23 ° C for one hour. This is then filtered and washed with ether which gives 8.7 grams of solid. This solid is then dissolved in 50 ml of ethanol and refluxed for two hours. The reaction mixture is cooled to room temperature and partitioned between 350 ml of chloroform and 200 ml of saturated sodium bicarbonate. The organic layer is separated and d over magnesium sulfate. The drying agent is filtered and the concentrate gives 5.3 grams of the product (70% yield).

MP: 105-106 ° O (M + H) 262.

STAGE 3: PREPARATION OF 5-METOXY-7.8-DIHYDRO-6H-3.4.8B-TRIAZA-AS-INDACENO-2-CARBALDEHÍDO 5.2 grams (19.8 mmol) of 5-methoxy-7,8-dihydro-6H-3,4,8-triaza-as-indacene-2-carboxylic acid ethyl ester are dissolved in 40 ml of dichloromethane and then cool to -78 ° C. Then add DIBAL (1 M, 30 ml, 1.5 equivalent) in a period of five minutes. The reaction medium is then quenched with 2 ml of ethanol and partitioned between 350 ml of dichloromethane and 100 ml of 1N sodium hydroxide. The aqueous layer is washed with another 150 ml of chloroform and the combined organic layer is d over magnesium sulfate and filtered and concentrated to give the corresponding alcohol. The alcohol is then dissolved in 150 ml of dichloromethane and then 10 grams of manganese dioxide are added. The mixture is stirred at 23 ° C for two hours. The reaction mixture is then filtered through a pad of celite and concentrated to give 1.1 grams (68%) of the desired aldehyde product. P.F.:235.2 ~ 236.3 ° C; MS. 218.1 (m + H).

Step 4: Preparation of 6- [acetoxy- (5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl) -methyl 4-nitrobenzyl ester ) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid To a solution of acetonitrile of 30 ml of 5-methoxy-7,8-dihydro-6H-3,4,8-triaza-as-indacene-2-carbaldehyde (660 mg, 3 mmol) is added 1.03 grams of etherate magnesium bromide. The mixture is stirred at 23 ° C for a half hour, then a 30 ml dry THF solution of 4-nitro-benzyl ester of d-bromo-7-oxo-4-thia-1-aza is injected. -bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1155 grams, 1 eq.) over a period of one minute and the reaction mixture is then cooled to -20 ° O then thylamine (0.7 ml) is injected , equivalents) and the reaction mixture is stirred for 5 hours at -20 ° C. Then acetic anhydride (0.377 ml, eq.) is injected and the reaction mixture is left at 0 ° C for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, 100 ml of saline. The organic layer is then d over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 1.8 grams of product. (93% Yield) P.F.:118.7-119, 1 ° C; MS: 645.9 (M + H).

Step 5: Preparation of 6- (5-methoxy-7.8-dihydro-6H-3.4.8b-triaza-as-5-2-yl) -methylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept acid -2-ene-2-carboxylic 4-Nitro-benzyl ester of 6- [acetyloxy- (5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-yl) -methyl) -6 is suspended -bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (966 mg, 1.4 mmol) in 20 ml of THF and 20 ml of aqueous phosphate buffer pH 6.5 . The mixture is then subjected to 45 psi hydrogen for 2 hours. This is then filtered through a pad of concentrated celite in vacuo to remove most of the THF. The solution is then cooled to zero degrees and basified to pH = 8 with 1N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% ~ 25% acetoniiril and water. The water is then stirred through the concentrate in vacuo and 100 mg of the product is collected.

PF: > 250 ° CH NMR: (300 MHz, D 2 O) d 10.12 (s, 1 H), 9.29 (s, 1 H), 8.81 (s, 1 H), 8.78 (S, 1 H), 6.19 (S, 3 H), 5.36 (m , 2H), 5.05 (m, 2H), 4.43 (m, 2H), MS. 371.2 (M + H).

EXAMPLE 27 Preparation of sodium salt, acid (5R.6Z) -6-f (5-r2- (benzyloxyethoxy1-7.8-dihydro-8H-cyclopentarelimidazoM, 2-pyrimidin-2-yl)) methylene) -7 -oxo-4-t a-1-azabicyclo3.2.01hept-2-ene-2-carboxylic acid: STEP 1: PREPARATION OF 4-BENZYLLOXYETOXY-6.7-DIHYDRO-5H-CICLOPENTAPYRIMIDIN-2-ILAMINE (SM: Ross, L; Goodman, L; Baker, B.R.J. Am. Chem. Soc. 1959, 81, 3108).

Slowly add to a stirred suspension of NaH (60% 552 mg) in THF of 2-benzyloxyethanol (3.38 g, 20 mmol) at room temperature. After the addition, 3.28 grams (19.4 μmol) of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine is dissolved in 200 ml of THF and added thereto and the mixture is refluxed for 3 hours . The solvent is then removed in vacuo and 100 ml of water is added to the residue. The product is extracted with chloroform; wash well with water and dry over anhydrous MgSO 4. This is filtered and concentrated. Solid of low melting point; Yield: 4.2 grams (73%); (M + H) 286.1.

Step 2: Preparation of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8-triaza-as-indacene-2-carboxylic acid ethyl ester. 6.0 grams (21 mmol) of 4-benzyloxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine are dissolved in 100 ml of dry THF. Then bromopyruvate (8 mL) is added dropwise in a period of 5 minutes. The mixture is stirred at 23 ° C for one hour. This is then filtered and washed with ether to give a solid. This solid is then dissolved in 50 ml of ethanol and refluxed for two hours. The reaction mixture is cooled to room temperature and partitioned between 350 ml of chloroform and 200 ml of saturated sodium bicarbonate. The organic layer is separated and dried over magnesium sulfate. The drying agent is filtered and the concentrate gives 5.36 grams of the product (66% yield). (M + H) 382.1.

STAGE 3: PREPARATION OF 5-BENCILOXIETOXI-7.8-DIHYDRO-6H-3.4.8B-TRIAZA-AS-INDACENO-2-CARBALDEHÍDO 3.81 grams (10 mmol) of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8-triaza-as-indacene-2-carboxylic acid ethyl ester are dissolved in 40 ml of dichloromethane and then cooled at -78 ° C. Then add DIBAL (1 M, 30 ml, 1.5 equivalents) in a period of five minutes. The reaction medium is then quenched with 2 ml of ethanol and partitioned between 350 ml of dichloromethane and 100 ml of 1N sodium hydroxide. The aqueous layer is washed with another 150 ml of chloroform and the combined organic layer is dried over magnesium sulfate and filtered and concentrated to give the corresponding alcohol. The alcohol is then dissolved in 150 ml of dichloromethane and then 10 grams of manganese dioxide are added. The mixture is stirred at 23 ° C for two hours. The reaction mixture is then filtered through a pad of celite and concentrated to give 2.25 grams (67%) of the desired aldehyde product. MS. 338 (m + H).

Step 4: Preparation of 4-nitro-benzyl ester of 6- [acetoxy- (5- [2- (benzyloxy) emethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indaceno- 2-yl) -methyl] -6-bromo-7-o? O-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid A solution of 30 ml of acetonitrile of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carbaldehyde is added. (376 mg, 2 mmol) to 1.03 grams of magnesium bromide etherate. The mixture is stirred at 23 ° C for a half hour. Then a dry THF solution of 30 ml of 4-nitrobenzyl ester of 6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid ester (770 mg, 2 mmol) are injected over a period of one minute and the reaction mixture is then cooled to -20 ° O. Triethylamine (0.7 ml equivalents) is then injected and the reaction mixture is stirred for five hours at -20 ° C. ° O Then acetic anhydride (0.377 ml eq.) Is injected and the reaction mixture is left at zero degrees for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, and 100 ml of saline. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 1.05 grams of the product. (68% yield); MS: 765.8 (M + H).

Step 5: Preparation of (5R.6Z) -6 - ((5-r2- (benzyloxy) ethoxy1-7.8-dihydroxy-6H-cyclopentare1imidazori.2-a1-pyrimidin-2-yl methylene) -7-oxo-4 acid thia 1l-azabicyclo3.2.01hept-2-ene-2-carboxylic acid: 4-Nitrobenzyl ester of 6 = [acetoxy- (5- [2- (benzyloxy) methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl is suspended) -methyl] 6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (966 mg, 1.2 mmol) in 20 ml of THF and 20 ml of a buffer of aqueous phosphate pH = 6.5. The mixture is then subjected to hydrogen at 45 psi for 2 hours. This is then filtered through a celiac pad and concentrated in vacuo to remove most of the THF. The solution is then cooled to zero degrees and basified to pH = 8 with 1N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% -25% acetonitrile and water. The water is then stirred through the concentrate in vacuo and 100 mg of the product is collected. PF: > 250 ° C; H NMR (DMSO) D 7.66 (s, 1H), 7.36 (s, 1H), 7.08 (M, 5H), 6.87 (s, 1H), 6.85 (S, 1H), 4.37 (m, 2H), 4.29 ( m, 2H, CH2), 3.65 (m, 2H, CH2), 2.73 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.02 (m, 2H CH2).

MS. 491.1. (M + H).

EXAMPLE 28 Preparation of sodium salt, acid (5R.6Z) -6- (2,3-dihydrorl31-azolo, 2-a1benzimidazol-6-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01hept-2- eno ° 2-cari oxílico STAGE 1: PREPARATION OF (2.3-DIHYDRO-BENZOI4.5MIDAZ? R2.1-B1TIAZOL-7-IL) -METANOL To a round bottom flask is added 2.83 grams of methyl ester of 2-thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid, 2.55 grams of dibromoethane and 50 ml of DMF and 50 ml of ethanol. The mixture is refluxed for 10 hours. Then it is concentrated to dry on a rotary evaporator. The solid is then dissolved in 100 ml of THF and 20 ml of 1 M LiAIH (in THF) is then injected over a period of five minutes. The reaction medium is stirred at room temperature for 1 hour. Ethanol (~ 10 mL) is then added, followed by 50 mL of 2N HCl. The aqueous layer is adjusted to a basic pH = 14 with 10N sodium hydroxide. The aqueous is extracted with 2x500 ml of ethyl acetate. The combined organic layers are dried over magnesium sulfate. The drying agent is filtered and concentrated yielding 2.04 grams (60%) of the product. MS: 207.0 (M + H). H NMR (DMSO) D 7.34 (m, 2H), 7.08 (m, 1H), 5.15 (m, 1H, OH), 4.53 (m, 2H, CH2), 4.34 (m, 2H, CH2), 4.00 (m , 2H, CH2).

Step 2: Preparation of 2,3-dihydro-benzo [4,5] imidazo [2,1-b] thiazole-7-carbaldehyde.

To a pre-cooled mixture (-50 - -60 ° C) of 1.7 ml of DMSO and 5 ml of dichloromethane is injected a solution of 20 ml of dichloromethane of 1 ml of oxalyl curedur in a period of 5 minutes. The mixture is stirred for other minutes at the same temperature. Then 1.9 grams of 2,3-dihydro-benzo [4,5] imidazo [2,1-b] thiazol-7-yl) -methanol is injected into a mixture of 20 ml of dichloromethane and 20 ml of THF in one period two minutes The mixture is kept under stirring at -50 ~ -60 ° C for 15 minutes. Then 7 ml of triethylamine is injected at once, and after another 5 minutes the cooling bath is removed and the reaction is heated to room temperature by itself. Then water (100 mL) is added and the reaction medium is extracted with 2x200 mL of ethyl acetate. The combined organic layers are dried over magnesium sulfate. The drying agent is filtered and the concentrate gives 1.2 grams of the product (64%). MS: 205.0 (M + H). H NMR (CDCl 3) G 9.98 (m, 1 H), 7.67 (m, 2 H), 7.17 (M, 1 H), 4.33 (m, 2 H), 3.99 (m, 2 H, CH 2).

Step 3: Preparation of 4-Nitro-benzyl ester of 6- (AcTtoxi- (2,3-di8nu-l-benzor-4-trifluoro-2-l-thiazol-6-yl) -methyl) -6-bromo-7-oxo-4 acid -t8a-1-aza-biciclor3.2.01hept-2-ene-2-carboxylic acid A solution of 30 ml of 2,3-dihydro-benzo [4,5] imidazo [2,1-b-thiazole-7-carbaldehyde (610 mg, 2 mmol) is added to 1.03 grams of magnesium bromide etherate. The mixture is stirred at 23 ° C for half an hour. Then a 30 ml dry THF solution of 4-nitrobenzyl ester of 6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (770) mg, 2 mmol) is injected over a period of one minute and the reaction mixture is then cooled to -20 ° 0. Triethylamine (0.7 ml equivalents) is then injected and the reaction mixture is stirred for five hours at -20 ° C. Then acetic anhydride (0.377 ml equivalents) is injected and the reaction mixture is left at 0 ° C for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, and 100 ml of saline. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 690 mg of the product. (54% Yield); MS: 730.8 (M + H) Step 4: Preparation of (5R-6Z) -6-dihydroxy-1,3-dihydroxy-3-azobenzimidazol-6-ylmethylene) -7-oxo-4-thia-1-azabicyclo3 .2.01hept-2-ene-2-carl © xyl 4-Nitrobenzyl ester of 6- [acetoxy- (2,3-dihydro-benzo [4,5] imidazo [2,1-b] thiazol-6-yl) -methyl] -6-bromo- acid is suspended. 7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (690 mg.1.1 mmol) in 20 mL of THF and 20 mL of aqueous phosphate buffer pH = 6.5. The mixture is then subjected to hydrogen at 45 psi for 2 hours.

This is then filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution is then cooled to 0 ° C and basified to pH = 8 with 1 N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% ~ 25% acetonitrile and water . The water is then stirred through the concentrate in vacuo and 32 mg of the product are collected. (3% yield). P.F .: > 250 ° C; H NMR (D2O) D 7.08 (m, 6H), 7.36 (s, 1 H), 4.05 (m, 2H), 3.90 (b, 1 H), MS. 358.3 (M + H).

EXAMPLE 29 Preparation of sodium salt, acid (5R-6Z) -6- (3,4-dihydro-2H-p.3Uiazinoyf3.2-a1benzimidazol-7-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01 Hept-2-ene-2-carb-xylic STAGE 1: PREPARATION OF (3.4-DIHYDRO-2H-1-TIA-4A.9-DIAZA-FLUOREN-6-ID-METANOL To a round bottom flask is added 4.06 grams of methyl ester of 2-thioxo-2,3-dihydro-1 H-benzoimidazole-5-carboxylic acid, 4.04 grams of 1,3-dibromopropane and 50 ml of DMF and 50 my ethanol The mixture is refluxed for 10 hours. Then it is concentrated to dry on a rotary evaporator. The solid is then dissolved in 100 ml of THF and 20 ml of 1M LiAIH (in THF) is then injected over a period of 5 minutes. The reaction medium is stirred at room temperature for one hour. Ethanol (~ 10 mL) is then added, followed by 50 mL of 2N HCl. The aqueous layer is adjusted to a basic pH = 14 with 10N sodium hydroxide. The aqueous is extracted with 2x500 ml of ethyl acetate. The combined organic layers are dried over magnesium sulfate. The drying agent is filtered and the proportion is concentrated by 3 grams (68%) of the product. NMR (DMSO) d 7.91 (m, 3H), 4.13 (m, 2H), 3.93 (s, 1 H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2), MS: 221.0 (M + H) Step 2: Preparation of 3,4-dihydro-2H-1-thia-4a.9-diaza-fluorene-6 ° carbaldehyde.

To a round bottom flask is charged with 1.1 grams of (3,4-dihydro-2H-1-thia-4a, 9-diaza-fluoren-6-yl) -methanol 6 grams of manganese dioxide and 250 ml of chloroform . The mixture is stirred for one hour at room temperature and then filtered through a pad of celite. This produces 0.67 grams of the product (61%). MS: 219.0 (M + H). H-NMR (CDCl 3) d 10.04 (s, 1 H), 7.67 (m, 3 H), 4.25 (m, 2 H), 3.27 (m, 2 H), 2.50 (m, 2 H) ).

Step 3: Preparation of (5R-) 6- (acetyloxy- (3,4-dihydro 2H-f1.3ltia:; "IOG, 2 ° albenzimidazol-7-1l) -metn-6-bromo-7-oxo-4 -thia-1-azabicyclo3.2.01hept-2-eri3) ° 2 ° carboxylate of 4-nitrobenzyl A solution of 30 ml of acetonitrile of 3,4-dihydro-2H-1-thia-4a-9-diaza-fluorene-6-carbaldehyde is added. (660 mg, 3 mmol) to 1.03 grams of magnesium bromide etherate. The mixture is stirred at 23 ° C for a half hour. Then a 30 ml dry THF solution of 4-nitrobenzyl ester of 6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.15 g, 3 mmol) are injected over a period of one minute and the reaction mixture is then cooled to -20 ° C. Triethylamine (0.7 ml eq.) is then injected and the reaction mixture is stirred for five hours at -20 ° C. ° Then acetic anhydride (0.377 ml equivalents) is injected and the reaction mixture is left at zero degrees for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, and 100 ml of saline. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 690 mg of the product. (36% of Performance); MS: 644.9 (M + H).

Step 4: Preparation of (5R-6Z) -6- (3,4-dihydro-2H-M.31-thiazira-Q3.2-a1-benzimidazol-7-ylmethylene) -7-oxo-4-thia-1-azabicyclo3.2.01heptide 2-ene-2-carboxylic (5R-) 6- (acetyloxy- (3,4-dihydro-2H- [1,3] thiazino [3,2-a] benzimidazol-7-yl) -methyl) -6- bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl.

Suspend (700 mg, 1.1 mmol) in 20 mL of THF and 20 mL of an aqueous phosphate buffer pH = 6.5. The mixture is then subjected to hydrogen at 45 psi for two hours. This is then filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution is then cooled to zero degrees and basified to pH = 8 with 1N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% ~ 25% acetonitrile and water. The water is then stirred through the concentrate in vacuo and 75 mg of the product are collected. (18% yield). PF: > 250 ° C; H NMR (D 2 O) δ 7.08 (m, 6H), 3.70 (m, 2H), 4.05 (m, 2H), 3.13 (m, 2H), 2.22 (m, 2H); MS: 372.1 (M + H).

EXAMPLE 30 Preparation of sodium salt, (5R-6Z) -7-oxo-6- (M.31tiazolor3.2-a1benei ™ dazol-8-ylmethylene) -4-thia-1-azabicyclo3.2.01hept-2- acid eno-2-carboxylic STAGE 1: PREPARATION OF ACID METHYL ESTER BENZ? R4.51IMIDAZ? R2.1-B1TIAZOL-6-CARBOXÍLICO To a round bottom flask is charged with 3.3 grams of methyl ester of 2-thioxo-2,3-dihydro-1 H-benzoimidazole-5-carboxylic acid, 4.5 ml of alpha-bromodiethyl acetal, 50 ml of DMF. The mixture is refluxed for 10 hours. It is then poured into 10% saturated sodium bicarbonate (100 mL) and extracted with 2x100 mL of ethyl acetate. The combined organic layers are dried over magnesium sulfate. The drying agent is filtered, concentrated to dryness, flash column chromatography was used with 10 to 30% ethyl acetate / hexane yielding 1.16 grams (32%) of the crude product. MS: 233.1 (M + H). H NMR (DMSO) d 7.78 (M, 5H), 2.04 (s, 3H, CH 3).

Stage 2: Preparation of benzo-r4.51imidazor2.1-b1tiazo8-6-earbaldei? It To a round bottom flask is charged with 1.16 grams of (3,4-dihydro-2H-1-thia-4a, 9-diaza-fluorene-6-yl) -methanol 25 grams of manganese dioxide and 250 ml of chloroform . The mixture is stirred for 1 hour at room temperature and then filtered through a pad of celite. This produces 0.42 grams of the product (42%). MS: 203.0 (M + H). H NMR (CDCl 3) d 10.10 (ss, 1 H), 8.24 (ss, 1 H), 7.85 (m, 3 H), 6.98 (m, 1 H).

Step 3: Preparation of f5R) -6-r (acetyloxy) - (ri.31thiazolor3.2-a1bencim5] azole 6-methyl) -6-bromo-7-oxo-4-thia-1-azabicyclo3.2.01hept- 2-ene-2-carboxylate of 4-nitrobenzyl A solution of 30 ml of benzo- [4] acetonitrile is added., 5] imy! Azo [2,1-b] thiazole-6-carbaldehyde (404 mg, 2 mmol) to 1.03 grams of magnesium bromide etherate. The mixture is stirred at 23 ° C for half an hour. Then a 30 ml dry THF solution of 4-nitrobenzyl ester of 6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (770) mg, 2 mmol) are injected over a period of one minute and the reaction mixture is then cooled to -20 ° O. Triethylamine (0.7 ml equivalents) is then injected and the reaction mixture is stirred for five hours at -20 ° O Acetic anhydride (0.377 ml equivalents) is then injected and the reaction mixture is left at zero degrees for 18 hours. The reaction medium is then diluted with 400 ml of ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml of saturated sodium bicarbonate, and 100 ml of saline. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl acetate in hexane gives 630 mg of the product. (50% yield); MS: 631.9 (M + H).

Step 4: Preparation of (5R-6Z) -7-oxo-6- (1,31-thiazoium-3,2-a-1-benzimidazol-6-ylmethylene) -4-thia-1-azabicyclo3.2.01hept-2-ene-2-earboxyl acid Suspend (5R) -6 - [(acetyloxy) - ([1, 3] thiazolo [3,2-a] benzimidazol-6-yl) -methyl) -6-bromo-7-oxo-4-thia-1 -zabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl (630 mg, 1 mmol) in 20 ml of THF and 20 ml of aqueous phosphate buffer pH = 6.5. The mixture is then subjected to hydrogen at 45 psi for two hours. This is then filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution is then cooled to 0 ° C and basified to pH = 8 with 1N sodium hydroxide. This is then purified by reverse phase HPLC using 1 liter of water followed by 5% ~ 25% acetonitrile and water. The water is then stirred through the concentrate in vacuo and 33 mg of the product are collected. (Yield 8%). P.F .: > 250 ° C; H NMR (D2O) d 6.89 (m, 8H), 5.22 (s, 2H), 5.02 (s, 2H), 4.81 (s, 2H).

MS. 378.1 (M + H + Na).

EXAMPLE 31 Preparation of sodium salt, (5R-6Z) -6- (7,8-dihydro-5H-pyranose 3-dlpyrazolor-5-bis-3-oxazol-2-ylmethylene) -7-oxo-4-thiazole acid 1-azabicyclo3.2.01heßt ° 2 ° ene ° 2 -carboxylic Step 1: Preparation of ethyl-5-r (4-oxotetrahydro-2H-pirar8-3-yl) -oxyl-1llH] -pyzole-3-carboxylate To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g potassium carbonate in 500 ml of acetonitrile 8.0 g of 3-bromo-tetrahydro-pyran-4 is added. -one, and reflowed for 16 hours. The reaction mixture is allowed to cool to room temperature, then filtered, the solid is washed with acetonitrile. The filtrate is concentrated to an oil. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over MgSO and evaporated to dryness. 9.0 g (78%) of the desired product is obtained as a white solid. P.F. 121-123 ° C (M + H) 255.

Step 2: Preparation of 7.8-dihydro-5H-pyranoi4.3-dlpirazoior5. 1f1.3lox ^: ethyl-ethylcarboxylate A mixture of ethyl 5 - [(4-oxotetrahydro-2H-pyran-3-yl) -oxy] -1H-pyra-ol-3-carboxylate (254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of acetic acid and toluene (50 mL) is refluxed for 18 hours using a Dean-Stark trap to remove the water. The reaction mixture is allowed to cool to room temperature. The reaction mixture is filtered. The filtrate is concentrated to an oil. The residue is dissolved in ethyl acetate, aqueous bicarbonate solution. The organic layer is washed with water and dried over MgSO. After removal of the ethyl acetate, the residue is purified by chromatography on silica gel eluting with ethyl acetate / hexane to give 120 mg (51%) of the desired product as a white solid. Pf; 116-118 ° C; Electrorociac-MS m / z 237.0 (M + H) +.

Stage 3: Preparation of 7.8-dih5dro-5H-pyranor4.3-d | pirazoor5. i PlH.31ox £. :: i 2 i? methanol It is added to the stirred solution of 7,8-dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazole-2-carboxylate (1.5 g, 3 mmol) in 100 g. mi of THF 1.05 g lithium brohydride and 1.54 g of methanol. The solution is heated at 40 C for 2.5 hours. The reaction is quenched with 1N HCl and adjusted to a pH of 1.3 and stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH 8 with K2CO3. The reaction mixture is extracted with ethyl acetate. The organic layer is dried over MgSO, and concentrated to an oil and column chromatographed to give 0.74 g of the desired product (60%). (M + H) 196.

Step 4: Preparation of 7.8-dihydro-5H-pyranor4.3-d1pyrazole5.1 biri.3loxaz® D-2-carbaldehyde.

It is added to the stirred solution of 7,8-dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazol-2-ylmethanol (1.0 g, 5.1 mmol) in 60 ml. my CHCL3 8g of MnO2. The suspension is refluxed for 1.5 hours under a nitrogen atmosphere. The reaction mixture is filtered through a pad of Celite. The filtrate is concentrated to give a yellow oil.

The product is purified by chromatography. Obtained 0.79 g of the product (80%) (M + H) 193.

Step 5: (5R) -6 - [(acetyloxy) (7,8-dihydro-5H-pyran [4,3] pyrazolo [5,1-b] [1, 3] oxezol-2-yl) -methyl] -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl. 7.8-Dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazole-2-carbaldehyde (600 mg, 3.1 mmol) is added successively and the solution in dry THF is added. (20 mL) 4-nitrobenzyl ester of (5R-6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid ester (1.54 g, 4.6 mmol) was added to the dry acetonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (2.21 g, 8.5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is carried to the next stage. Pale yellow amorphous solid; Yield: 1.35 g, 70%; (M + H) 619.

Step 6: Preparation of sodium salt, (5R-6Z) -6- (7.8-dihydro-glHl-pyranor4.3-d1pyrazolor5.1-biri.31oxazol-2-ylmethylene) -7-oxo-4-thia acid 1st azabicyclo3.2.01hept-2-ene-2-carboxylic & sodium salt, acid (5R-6SD-6HÍ7.3-dihydro-5H-pyranor4.3-d1pyrazolof5.1-b1M.31oxazol-2-ylmethylene) -7-oxo-4-thia ° 1] -azabicyclo3.2.01hept -2-ene-2-carboxylic It dissolves (5R) -6- [acetyloxy- (7,8-dihydro-5H-pyrano- [4,3-d] pyrazolo [5,1-b] [1, 3] oxezol-2-yl) -methyl ) -6-bromo-7-oxo-4-aia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl (1.2 g, 1.9 mmol) in THF (20 mL), acetonitrile (10 mL) and 0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% PD / C at a pressure of 40 psi. After 4 hours the reaction mixture is filtered, cooled to 3 ° C, 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin.

Initially the column is eluted with deionized water (2 liters) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. In this reaction both E and Z isomers are formed and they are separated by preparative HPLC.

Sodium salt, (5R-6Z) -6- (7,8-dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazol-2-ylmethylene acid ) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic: Yield 87 mg (25%); yellow solid; (M + H + Na) 368.2.

H NMR (D2O): 7.04 (1H, s), 7.01 (1H, s), 6.45 (1H, s), 6.09 (1H, s), 4.76 (2H, m), 4. 12 (2H, m), 2.96 (2H, m) Sodium salt, (5R, 6E) -6- (7,8-Dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1,3] oxazol-2-ylmethylene) acid - 7-Oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic: Yield 75 mg (21%); yellow solid; (M + H + Na) 368.2.

H NMR (D2 O): 7.08 (1H, s), 6.81 (1H, s), 6.71 (1H, s), 6.40 (1H, s), 4.68 (2H, m), 4.03 (2H, m), 287 (2H, m).

EXAMPLE 32 Preparation of sodium salt, (5R.6Z) -7-oxo-6- (5.6.7.8-tetrahydropyrazeflof.5.1- biri.3lbenzoxazol-2-yl) methylene) - 4-thia-1-azabicyclo3 acid. 2.01hept-2-ene-2-carboxylic Step 1: Preparation of ethyl-5-r (2-oxocyclohexyl) oxy-1H-pyrazole-3-carisoxylate It is added to the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (6.25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature, then filtered, the solid is washed with acetonitrile. The filtrate is concentrated to an oil. The residue dissolves e? ethyl acetate and extracted with water. The organic phase is dried over MgSO 4 and evaporated to dryness. The product is purified by silica gel column chromatography by eluting with 1: 1 ethyl acetate: hexane. 4.92 g (49%) of the desired product is obtained as a white solid. P.F. 122-124 ° C (M + H) 253.

Step 2: Preparation of 5.6.7.8-tetrahydropyrazole 5,1 ° bin.31benzoxazole-2 ° ethyl carboxylate A mixture of ethyl 5 - [(2-oxoxycyclohexyl) -oxy] -1H-pyrazole-3-carboxylate. (127.6 mg , 0.5 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid and toluene (50 mL) is refluxed for 18 hours using a Dean-Stark trap to remove the water. The reaction mixture is allowed to cool to room temperature. The reaction mixture is filtered. The filtrate is concentrated to an oil. The residue is dissolved in ethyl acetate and aqueous bicarbonate solution. The organic layer is washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue is purified by silica gel chromatography eluting with 1: 1 ethyl acetate / hexane to give 69.7 mg (59%) of the desired product as a white solid. P.F. 55-57 ° C; Electroroated-MS m / z 235.0 (M + H) +.

Step 3: Preparation of 5.6.7.8-tetrahydropyrazolor5.1-bip.31benzoxazole-2-5B? Praetanol To the stirred solution of ethyl 5,6,7,8-tetrahydropyrazolo [5, 1-b] [1, 3] benzoxazole-2-carboxylate (3.84 g, 16.4 mmol) in 100 mL of THF 3.05 g of lithium borohydride and 3 ml of methanol. The solution is heated at 40 ° C for 2.5 hours. The reaction is quenched with 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH 8 with K2CO3. The reaction mixture is extracted with ethyl acetate. The organic layer is dried over MgSO, and concentrated to an oil and column chromatographed to give 2.62 g of the desired product (83%). P.F. 82-84 ° C; (M + H) 193.

Stage 4: Preparation of 5.6.7.8-tetrahydropyrazolor5.1-b1f1.31benzoxazole-2-carbaldehyde To the stirred solution of 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] benzoxazol-2-ylmethanol (2.30 g, 11.97 mmol) in 60 ml of CHCl 3 is added 10 g of MnO 4. The suspension is refluxed for 1.5 hours under a nitrogen atmosphere. The reaction mixture is filtered through a pad of Celite. The filtrate is concentrated to give a yellow solid. The product is purified by chromatography. Obtain 1.95 g of the product (85.5%); (M + H) 191.

Step 5: (5R) -6-r (acetyloxy) (5.6.7.8-tetrahydropyrazolor5.1-bip.31benz-xazo8-2-yl) methyl-6-bromo-7-oxo-4-thia-1-azabicyclo3. 2.01hept-2-ene-2-carboxylate 4-nitrobenzyl.

Successively add 5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] benzoxazole-2-carbaldehyde (589 mg, 3.1 mmol) and the solution in dry THF (20 mL) of 4-methyl ester. -nitro benzyl acid (5R, 6S) -6-bromo-7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid (1.54 g, 4.6 mmol) a Dry acetonitrile solution (15 mL) of anhydrous MgBr 2: O (Et) 2 (2.21 g, 8.5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate: hexane (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is carried to the next stage. Pale yellow amorphous solid; Yield: 792 mg, 42%; P.f. 160-162 ° O (M + H) 618.

Step 6: Preparation of sodium salt, acid (5R.6Z) -7 ° oxo-6- (5.6.7.8 ° tetrahydropyrazolor5.1-bin.31benzoxazol-2-yl) methylene)) - 4-thia-1-azabicyclo3 .2. 2-ene-2-carboxylic acid It is dissolved (5R) -6 - [(acetyloxy) (5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] benzoxazol-2-yl) methyl-6-bromo-7-oxo- 4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate of 4-nitrobenzyl (318 mg, 0.5 mmol) in THF (20 mL), acetonitrile (10 mL) and 0.5 m phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% PD / C (100 mg) at a pressure of 40 psi . After 4 hours the reaction mixture is filtered, cooled to 3 ° C, 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin. Initially the column is eluted with deionized water (2 liters) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. Yield 150 mg (76%); yellow solid; (M + H + Na) 365.2.

H NMR (D2 O): d 6.92 (1 H, s), 6.91 (1 H, s), 6.32 (1 H, s), 5.85 (1 H, s), 2.59 (4H, m), 1.80 (4H , m).

EXAMPLE 33 Preparation of sodium salt, acid (5R.6Z) -6- (r6- (ethoxycarbonyl1-5.β.7-tetrahydropyrazolor5'.1 ': 2.3iri.31oxazolor5.4-c1pyridin-2-yl) methylene) ) -7-oxo-α-1- azabicyclo3.2.01hept-2-ene-2-carboxylic acid Step 1: Preparation of 3- r6- (ethoxycarbonylMH-pyrazol-g-yl) oxyM "oxypiperidine-1-ethyl carboxylate.

It is added to the stirred suspension of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (19.5 g, 127 mmol) and 50.0 g of potassium carbonate in 500 ml of acetonitrile 3-bromo-4-ethyl ester -oxo-piperidine-1-carboxylic acid (37.45 g, 149 mmol), and refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature, then filtered, the solid is washed with acetonitrile. The filtrate is concentrated until it reaches an oil. The residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried over MgSO 4 and evaporated to dryness. The product is purified by silica gel column chromatography by eluting with 1: 1 ethyl acetate: hexane. 8.5 g (19%) of the desired product is obtained as a yellow oil. (M + H) 326.

Step 2: Preparation of 7,8-tetrahydropyrazolor 5M ': 2.3in.31oxazolor5.4-e1iQin ñna ° 2.6 (5H) -dicarboxylate diethyl ester.

A mixture of 3-. { [3- (ethoxycarbonyl) -1 H -pyrazol-5-yl) oxy} Ethyl -4-oxypiperidine-1-carboxylate (325 mg, 1 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid and toluene (50 mL) is refluxed for 18 hours using a Dean-Stark trap to remove Water. The reaction mixture is allowed to cool to room temperature. The reaction mixture is filtered. The filtrate is concentrated to an oil. The residue is dissolved in ethyl acetate and a solution of aqueous bicarbonate. The organic layer is washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue is purified by silica gel chromatography eluting with 1: 1 ethyl acetate / hexane to give 175 mg (57%) of the desired product as a yellow oil. Electroroated - MS m / z 308.0 (M + H) +.

Step 3: Preparation of 2- (hydroxymethyl) -7,8-dihydropyrazolor 5'.1 ': 2.3iri.31oxazoior5.4-c1pyridine-6 (5H) -carboxylate ef To the stirred solution of 7,8-tetrahydropyrazolo [5 ', 1': 2.3] [1, 3] oxazolo [5,4-cjpyridine-2,6 (5H) -dicarboxylate diethyl ester (307 mg, 1 mmol) in 40 ml of THF it is added to 305 mg of lithium borohydride and 1 ml of methanol. The solution is heated to 40 ° C for 2.5 hours. The reaction is quenched with 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH 8 with K2CO3. The reaction mixture is extracted with ethyl acetate. The organic layer is dried over MgSO4, and concentrated to an oil and column chromatographed to give 172 mg of the desired product (65%) (M + H) 266.

Step 4: Preparation of 2-formyl-7,8-dihydropyrazolor 5'.1 ': 2.3in.3loxazolofS.4-c1pyridine-6 (5H) -carboxylate ethyl To the stirred solution of 2- (hydroxymethyl) -7,8-dihydropyrazolo [5 ', 1': 2.3] [1, 3] oxazolo [5,4-c] pyridine-6 (5H) -carboxylic acid ethyl ester (1.76 g, 6.6 mmol) in 60 ml of CHCl3 are added 10 g of MnO2. The suspension is refluxed for 1.5 hours under a nitrogen atmosphere. The reaction mixture is filtered through a Celifa pad. The filtrate is concentrated to give a yellow solid. The product is purified by chromatography. Obtained 1.43 g of the product (82%); P.f .: 97-99 ° C (M + H) 264.

Step 5: Preparation of 2 - [(acetyloxy) (5R) -6-bromo-2-Z. { [(4-Nitrobenzyl) oxy] carbonyl} -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-6-yl) methyl) -7,8-dihydropyrazolo [5M ': 2,3] [1, 3] oxazolo [ 5,4-c] pyridine-6 (5H) -ethylcarboxylate. 2-Formyl-7,8-dihydropyrazolo [5 ', 1': 2.3] [1, 3] oxazolo [5,4-c] pyridine-6 (5H) -carboxylic acid ethyl ester (790 mg, 3 mmol ) and the solution in dry THF (20 mL) of 4-nitrobenzyl ester of (5R, 6S) -6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-acid. eno-2-carboxylic (1.54 g, 4.6 mmol) was added to the solution of dry acetonitrile (15 mL) of anhydrous MgBr 2: O (Et) 2 (2.21 g, 8.5 mmol) under an argon atmosphere at room temperature. After cooling to -20 ° C, Et3N (2.0 mL) is added in one portion. The reaction vessel is covered with a foil to isolate it from light. The reaction mixture is stirred for 2 h at -20 ° C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture is warmed to 0 ° C and stirred for 15 h at 0 ° C. The mixture is diluted with ethyl acetate and washed with an aqueous solution of 5% citric acid, saturated sodium hydrogen carbonate, and saline. . The organic layer is dried (MgSO4) and filtered through a pad of Celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is applied to silica gel column chromatography, and then the column is eluted with ethyl acetate (hexane) (1: 1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers is carried to the next stage. Pale yellow amorphous solid; Yield: 1.67 g, 81%; (M + H) 690.

Step 6: Preparation of sodium salt, acid (5R, 6Z) -6-fr6 ° (etox¡earbapW ° 5. 6.7.8-tetrahydropyrazolor5'1 ': 2.31f1.31oxazolor5.4-clpiridin-2-yl) methylene and -7- [beta] -4-thia-1-azabicyclo3.2.01hept-2-ene-2-carboxylic acid 2 - [(acetyloxy) (5R) -6-bromo-2-Z ([(4-nitrobenzyl) oxy] carbonyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2 -ne-6-yl) methyl) -7,8-dihydropyrazolo [5 ', 1': 2.3] [1,3] oxazolo [5,4-c] pyridine-6 (5H) -ethylcarboxylate (828 mg, 0.5 mmol) is dissolved in THF (20 mL), acetonitrile (10 mL) and 0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% of PD / C (200 mg) to a 40 psi pressure. After 4 hours the reaction mixture is filtered, cooled to 3 ° C, 0.1 N NaOH is added to adjust the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer is separated. The aqueous layer is concentrated under high vacuum at 35 ° C to give a yellow precipitate. The product is purified by reverse phase column chromatography with HP21 resin, initially the column is eluted with deionized water (2 L) and finally with 10% acetonitrile: water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature.

The yellow solid is washed with acetone and filtered. Yield 375 mg (71%); yellow solid; (M + H + Na) 438.4.

H NMR (D2O): d 6.96 (1H, s), 6.94 (1H, s), 6.41 (1H, s), 6.00 (1H, s), 4.53 (2H, m), 4.13 (2H, q), 3.78. (2H, m), 2.78 (2H, m), 1.21 (3H, t).

Brief Description of Two Biological Test Procedures and the Text Summary of the Results.

Antimicrobial Susceptibility Test. The in vitro activities of the antibiotic, in this case piperacillin, against resistant pathogens expressing class D enzymes are determined by the microcalcium dilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS). (NCCLS 2000. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, Approved Standards: M7-A5, Vol 19. National Committee for Clinical Laboratory Standards, Villanova, PA). The Mueller-Hinton II (MHBII) broth (BBL Cockeysville, MD) is used for the test procedure. Microtiter plates containing 50 μl per well of two-fold piperacillin serial dilutions combined with a constant amount (4 μg / ml) of a β-lactamase inhibitor (final concentration) were incubated with 50 μl inoculated to produce the density appropriate (105 CFU / ml) in 100 μl. The plates are incubated for 18 to 22 hours at 35 ° C in ambient air. The minimum inhibitory concentration (MIC50) for all isolates was defined as the lowest concentration of antimicrobial agent that completely inhibits the growth of the organism as detected by the unaided eye. The MIC data obtained by the above mentioned procedure are listed in Table 1. As a control piperacillin it has a MIC50 value > 64 μg / MI. Both oxa-10 and PSE-2 are class D β-lactamases (Busk, K, Jacoby, G.A., Medeiros, A.A. Antimicrob, Agents Chemother, 1995, 39.1211).

Table 1: Minimum inhibitory concentration (MIC50) data (μg / mL): fliroc: 35 ° € for 18 hours.

Against organisms E. Cois GC 2883 (OXA-10 + PSE-2) that produce CDas © D.

Control: piperacillin; MIC50 value for piperacillin > 84 μg / ml

Claims (1)

1. CLAIMS A method for inhibiting Class D enzymes in the treatment of bacterial infection in a patient in need thereof comprising supplying an effective amount of a compound of formula I wherein one of A and B denote hydrogen and the other an optionally substituted fused tricyclic heteroaryl group; X is S or O; R5 is H, alkyl, C1-C6, C5-C6 cycloalkyl, alkyl CHR3OCOC1-C6; Y R3 is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. The method according to claim 1 wherein the tricyclic heteroaryl group has the formula 1-A 1-B where Z, Z2, Z3, Z ^ Z5, Ze, and Z7, are independently CR2, N, O, S or N-Ri since one of Z Z7 is a carbon atom to which the rest of the molecule is attached; Ri is H, alkyl is optionally substituted, optionally substituted aryl, optionally substituted heteroaryl or saturated mono or bicyclic heterocycles, optionally substituted cycloalkyl, optionally substituted alkenyl, alkynyl optionally substituted with the proviso that double bond and triple bond should not be present in the carbon atom that is directly bound to N; optionally substituted perfluoroalkyl, alkyl or aryl optionally substituted by -S (O) p wherein p is 0-2, -C = O optionally substituted heteroaryl, C = O optionally substituted aryl, - C = O alkyl, optionally substituted, -C = Or optionally substituted cycloalkyl, optionally substituted monocyclic or bicyclic heterocyclic C, optionally substituted C 1 -C 6 alkylaryl, optionally substituted C 1 -C 6 alkylheteroaryl, optionally substituted C 1 -C 6 alkyl, optionally substituted heteroaryl C 1 -C 6 alkyl, heterocycles saturated monomers or bicyclics C1-C6 alkyl optionally substituted, arylalkenyl of 8 to 16 carbon atoms optionally substituted, -CONR6R, -SO2NR6R7, arylalkyl optionally substituted, -alkyl-O-alkyl-aryl optionally substituted, -alkyl-O-alkyl, -heteroaryl, optionally substituted, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, aryloxyhete optionally substituted roaryl, optionally substituted C 1 -C 6 alkylaryloxyaryl, optionally substituted C 1 -C 6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryl carbonyl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted, halogen, cyano, N-R6R7, optionally substituted hydroxy C1-C6 alkoxy; optionally substituted aryl, optionally substituted heteroaryl, COORß, optionally substituted alkylaryloxyalkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, aryloxy- C1-C6 optionally substituted alkyl amine, perfluoro C1-C6 alkyl, C1-C6 alkyl optionally substituted by S (O) q-, aryl optionally substituted by, S (O) q- where q is 0, 1 or 2, CONR6R7, guanidino or cyclic guanidino, optionally substituted alkylaryl, optionally substituted arylalkyl, optionally substituted C 1 -C 6 alkylheteroaryl, optionally substituted heteroarylC 1 -C 6 alkyl, mono or bicyclic saturated optionally substituted C 1 -C 6 alkyl heterocyclic, arylalkenyl of 8 to 16 carbon atoms optionally substituted, SO2NR6R7, arylalkyloxyalkyl optionally substituted, aryloxyalkyl optionally their substituted, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted heteroaryloxyaryl, optionally substituted C 1 -C 6 aryloxyaryl, optionally substituted C 1 -C 6 alkylaryloxyheteroaryl optionally substituted, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkineamine; Rβ and R7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R6 and R can together with the N to which they are attached, can form a saturated ring system of 3 to 7 members said ring system in addition to the N to which R6 and R are adhered optionally have one or two additional heteroatoms selected from N-Ri , O, S (O) "n = 0-2; Y Yi, Y2, Y3 and Y4 can independently be C or N. The method according to claim 1 wherein the tricyclic heteroaryl group is kh 2-B where Z1 t Z2, Z3, Z4, Z5, Ze, Z7, and Z8 are independently CR2, N, O, S or N-R, since one of Z Z8 is a carbon atom to which the remainder of the molecule is attached; and R1 t R2, R6, R7 Y ,, Y2, Y3 and Y are as defined in claim 2; The method according to claim 1 wherein the heterocyclic heterocyclic group is ££ where Z1 t Z2, Z3, Z4, Z5, Z6, Z7 and Z8 are independently CR2, N, O, S or N- R since one of them is a carbon atom to which the rest of the molecule is attached; R1 f R2, R1, R7, Yi, Y2, Y3 and Y are as defined in claim 2; The method according to claim 1 wherein the tricyclic heteroaryl group is 4-A 4-B where Z1 (Z2, Z3, Z4, Z5, Z6, Z7, Z8, and Z9 are independently CR2, N, O, S or NR! since one of the Z1-Z9 is a carbon atom to which the remainder of the molecule is adhered, R1t R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2; The method according to claim 1 wherein the tricyclic heteroaryl group is where Z, Z2, Z3 and Z ^ are independently CR2, N, O, S or N-R! and since one of the Z-Z, is a carbon atom to which the rest of the molecule is attached; W ,, W2 and W3 are independently CR R4, S (O) r (r = 0-2), O, N-Ri with the proviso that no SS, SO or O-O bond formation can occur to form a saturated ring; R 2 R 2, R 7, R 7, Y 1t Y 2, Y 3 and Y 4 are as defined in claim 2; R is H, optionally substituted C1-C6 alkyl, OH (since both R are not OH), C1-C6 alkoxy, -S- C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7; or R4R4 can be = O or RR together with the carbon to which they are attached form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n (where n = 0 a 2), N-R1; and t = 1 to 3. The method according to claim 1 wherein the tricyclic heteroaryl group is wherein Z \, Z2, Z3, Z and Z5 are independently CR2, N, O, S or -Ri since one of the Z ^ Zs is a carbon atom to which the rest of the molecule is attached; Yi, and Y2 are independently C or N; W ,, W2 and W3 are independently CR 4R, S (O) r (r = 0-2), O, NR, with the proviso that no SS, SO or O-O bond formation can occur to form a saturated ring; R ^ R2, R6, and R7, are as defined in claim 2; R 4 is H, optionally substituted C 1 -C 6 alkyl, OH (since both R 4 are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COOR 6, -NR 6 R 7, -CONR 6 R 7; or R, R4 can be = O or RR together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of selected heteroatoms of N, O, S (O) n (where n = 0 to 2), N-R1; and t = 1 to 3. The method according to claim 1 wherein the tricyclic heteroaryl group is 7-B where Zi, Z2, Z3, Z, Z5 and Zß are independently CR2, N, O, S and N-R? since one of Z Ze is a carbon atom to which the rest of the molecule is attached; W ?, and W2 are independently CR4R4? S (O) r (r = 0-2), O, H-R with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; R1 t R2, R6, R7, Yi, Y2, Y3 and Y are as defined in claim 2; R is H, optionally substituted C 1 -C 6 alkyl, OH (since both R are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COOR 6, -NR 6 R 7, -CONR 8 R 7; or R, R4 can together be = O or R R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n ( where n = 0 to 2), N-R1; and T = 1 to 3. The method according to claim 1 wherein the tricyclic heteroaryl group is & A &g where Z1 t Z2, Z3, Z, Z5, Ze and Z7 are independently CR2, N, O, S or NR? since one of Z Z7 is a carbon atom to which the rest of the molecule is attached; W ,, and W2 are independently CR4R, S (O) r (r = 0-2), O, N-RI with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; Ri. R2 > Rß > R7, Y? > Y2 Y3 and Y are as defined in claim 2; or optionally R is H, optionally substituted C 1 -C 6 alkyl, OH (since both R 4 are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COOR 6, -NR 6 R 7, - CONR 6 R 7; or RR can together be = O or R4R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of selected heteroatoms of N, O, S (O) n (where n = 0 to 2), N-R1; and t = 0-3. The method according to claim 1 wherein the tricyclic heteroaryl group is? # wherein Z1f Z2 and Z3 are independently CR2, N, O, S or N-R? since one of Z Z3 is a carbon atom to which the rest of the molecule is attached; Yi and Y are independently C or N; Y2 and Y3 are independently CH or N; WL W2, W3, W4 and W5 are independently CR4R, S (O) r (r = 0-2), O, N-Ri with the proviso that no SS, SO or OO bond formation can occur to form a saturated ring; R ?, R2. Re. And R7, are as defined in claim 2; R4 is H, optionally substituted C1-C6 alkyl, OH (since both R are not OH), C1-C6 alkoxy, -S-C1-C6 alkyl, COORß, -NR6R7, -CONR6R7; or R, R4 can together be = O or R R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n ( where n = 0 to 2), N-R1; t = 1 to 2; and u = 1 to 3. The method according to claim 1 wherein the tricyclic heteroaryl group is 0 ^ 10-e where Z1 f Z2, Z3, Z4, Z5? Z6, Z7, Z8 and Z9 are independently CR2, N, O, S or is a carbon atom to which the rest of the molecule is attached; R1, R2, R6, R, Y ^, Y2, Y3 and Y are as defined in claim 2; The method according to claim 1 wherein the tricyclic heteroaryl group is where Z1, Z2, Z3, Z4? Z5, Z6, Z7, Z8, Z9 and Z10 are independently CR2, N, O, S or N-R ^ since one of the Z? -Z10 is a carbon atom to which the rest of the molecule is attached; R1 t R2I R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2; The method according to claim 1 wherein the tricyclic heteroaryl group is i? § where Zi, Z2, Z3, Z ^ "and Z5 are independently CR2, N, O, S or N-R? since one of Z Z5 is a carbon atom to which the rest of the molecule is attached; Wi, W2 and W3 are independently CR R? S (O) r (r = 0-2), O, N-RÍ with the proviso that no formation of S-S, S-O or O-O bond can occur to form a saturated ring; and R ,, R2, Rβ, R7, Y ,, Y2, Y3 and Y4 are as defined in claim 2; R 4 is H, optionally substituted C 1 -C 6 alkyl, OH (since both R 4 are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COOR 6, -NR 6 R 7, -CONR 6 R 7; or R, R can together be = O or R, R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n (where n = 0 to 2), N-R1; and t = 1 to 4. The method according to claim 1 wherein the tricyclic heteroaryl group is 1AA 13-B ls c where since one of Z 2 Ze is a carbon atom to which the remainder of the molecule is attached; W ,, W2 and W3 are independently CR 4R4, S (O) r (r = 0-2), O, N-R? with the proviso that no S-S, S-O or O-O bond formation can occur to form a saturated ring; Ri, R2, Rß > R7, Y1, Y2. Y3 and Y4 are as defined in claim 2; R is H, optionally substituted C 1 -C 6 alkyl, OH (since both R are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COOR 6, -NR 6 R 7, -CONR 6 R 7; or R4R4 can be together = O or R4R together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n (where n = 0 to 2), N-R1; t = 1 to 3. . The method according to claim 1 wherein the tricyclic heteroaryl group is 1 14-B kC wherein Z, Z2, Z3, Z4, Z5, Zß, Z7 and Z8 are independently CR2, N, O, S or N-R1; since one of Z? -Z8 is a carbon atom to which the rest of the molecule is attached; W ?, and W2 are independently CR4R4? S (O) r (r = 0-2), O, - with the proviso that no bond formation S-S, S-O or O-O can occur to form a saturated ring; R1 R2. Re, R7, Y1, Y2 > Y3 and Y are as defined in claim 2; R4 is H, optionally substituted C1-C6 alkyl, OH (since both R are not OH), C1-C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7; or R, R4 can together be = O or R4R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n (in where n = 0 to 2), N-R1; t = 1 to 2. . The method according to claim 1 wherein the heterocyclic heterocyclic group is where Z1 t Z2, Z3 and Z *, are independently CR2, N, O, S or N-R ^ given that one of Zi-Z ,, is a carbon atom to which the rest of the molecule is attached; W1 (W2, W3, W4 and W5 are independently CR4R4, S (O) r (r = 0-2), OR, NR with the proviso that no SS, SO or OO bond formation can occur to form a ring saturated; R1 R2, R > R7, Y? > Y2 > Y3 and Y4 are as defined in claim 2; R is H, optionally substituted C 1 -C 6 alkyl, OH (since both R 4 are not OH), C 1 -C 6 alkoxy, -S-C 1 -C 6 alkyl, COORe, -NR 6 R 7, -CONR 6 R 7; or R4R4 can together be = O or R4R4 together with the carbon to which they are attached can form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S (O) n (where n = 0 to 2), NR ,, t = 1 to 3; and u = 1 to 3 The method according to any one of claims 1 to 16 wherein the compound has the formula 18. The method according to any one of claims 1 to 17 wherein X is S. 19. The method according to claim 1 wherein the compound is selected from the group consisting of (5R, 6Z) -6- (lmidazo [2,1-b] [1,3] benzothiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-acid eno-2-carboxylic; (5R, 6Z) -6 - [(7-methoxyimidazo [2,1-b] [1,3] benzothiazol-2-methylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept -2-ene-2-carboxylic acid; (5R, 6Z) -6 - [(7-Chloroimidazo [2,1-b] [1,3] benzothiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept -2-ene-2-carboxylic (5R), (6Z) -6-lmidazo [1, 2-a] quinolin-2-ylmethylene-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; (5R), (6Z) -6- (6,7-Dihydro-5H-cyclopenta [d] imidazo [2,1-b] [1,3] thiazol-2-ylmethylene) -7-oxo-4- (5R) acid thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; sodium salt, acid (5R), (6Z) -6- (lmidazo [1,2-a] chenoxalin-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hepto-2-ene -2-carboxylic; (5R, 6Z) -6 - [(7-Methylimidazo [2, 1-b] [1, 3] benzothiazol-2-ylmethylene) -7-o? o-4-thia-1-azabicyclo [3.2.0] ] hept-2-ene-2-carboxylic acid; sodium salt of (5R), (6Z) -6- (4,5,6,7-tetrahydro-1,3a, 3b, 8-tetraaza-cyclopenta [a] indene-2-ylmethylene) -7-oxo acid -4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid; (5R, 6E) -6 - [(10-Benzyl-11-oxo-10,11-dihydrodibenzo [b, f] [1,4] oxazepin-8-yl) methylene] -7-oxo-4-tia -1-azabicyclo [3.2.0] hept-2-ene-2-carbo-yl; 6- (5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene) -7-o? o-4-thia-1-aza-bicyclo acid [3.2 .0] hept-2-ene-2-carboxylic acid; sodium salt, acid (5R, 6E &Z) -7-oxo-6- (4H, 10H-pyrazolo [5,1-c] [1,4] benzo [azepin-2-ylmethylene) -4-thia- 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; sodium salt of (5R), (6Z) -6- (5H-lmidazo [2,1-a] isoindol-2-ylmethylene) -7-oxo-4-thia-1-aza-bicyclo [3.2.0] ] hept-2-ene-2-carboxylic acid; (5R, 6Z) -6 - [(5-Methylimidazo [2,1-b] [1,3] benzothiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept -2-ene-2-carboxylic acid; (5R, 6Z) -6 - [(7-Fluoroimidazo [2,1-b] [1,3] benzothiazol-2-ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept -2-ene-2-carboxylic acid; (5R), (6Z) -6- (5,8-Dihydro-6H-imidazo [2,1-b] pyran [4,3-d] [1,3] thiazol-2-ylmethylene) -7- acid oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; acid (5R), (6Z) -6- (imidazo [2,1-b] bebzothiazol-7-ylmethylene) -7-o? o-4-thia-1-azabicyclo [3.2.0] hept-2-ene -2-carboxylic; (5R), (6Z) -7-oxo-6 - ([1,3] thiazolo [3,2-a] benzimidazol-2-ylmethylene) -4-thia-1-azabicyclo [3.2.0] hept- 2-ene-2-carboxylic acid; (5R), (6Z) -6- (7,8-Dihydro-6H-cyclopenta [3,4] pyrazolo [5,1-b] [1,3] thiazol-2-ylmethylene) -7-oxo- 6-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carbo-yl; (5R), (6Z) -7-Oxo-6- (5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-ylmethylene) -4-thia-1-acid azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; (5R), (6Z) -8 - [(9-methyl-9H-imidazo [1, 2-a] benzimidazol-2-yl) methylene] -7-oxo-4-thia-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylic acid; (Sodium salt) acid (dR.eZH-oxo-e ^ H-thieno ^ '. S' ^. Djtiopirano ^. S-bjpiridin-2-ylmethylene) -4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; (Sodium salt) of (5R, 6Z) -7-oxo-6- (4H-thieno [2 ', 3': 4,5] thiopyrano [2,3-b] pyridin-2-ylmethylene) acid -4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -6 - [(5-methyl-7,8-dihydro-6H-cyclopenta [e] [1, 2,4] triazolo [1,5-a] pyrimidin-2-acid) il) methylene] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, acid (5R, 6Z) -6-. { [7- (ethoxycarbonyl) -6,7,8,9-tetrahydropyrido [3,4-e] [1,2,4] triazolo [1,5-a] pyrimidin-2-yl] methylene} -7-oxo-4-thia-1-azabicyclo [3.2.0) hept-2-ene-2-carboxylic acid; Sodium salt of acid (SR.ez ^ - ^ '.?' - dihydro-T? -espirop.S-dioxolane ^ y- [1, 2,4] triazolo [1, 5-a] quinazolin] -2 ' -ylmethylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt of (5R, 6Z) -6 - [(5-methyl-6,7,8,9-tetrahydro [1,2,4] triazolo [1, 5-a] quinazolin-2-yl) methylene acid ] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carbo-yl; Sodium salt of (5R, 6Z) -6 - [(5-methoxy-7,8-dihydro-6H-cyclopenta [e] imidazo [1, 2-a] pyrimidin-2-yl) methylene] -7- acid oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -6- (. {5- [2- (benzyloxy) ethoxy] -7,8-dihydro-6H-cyclopenta [e] imidazo [1,2-a] pyrimidine acid 2-yl.} Methylene) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt of acid (5R, 6Z) -6- (2,3-dihydro [1,3] thiazolo [3,2-a] benzimidazo! -6-ylmethylene) -7-oxo-4-thia-1- azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -6- (3,4-dihydro-2H- [1,3] thiazino [3,2-a] benzimidazol-7-ylmethylene) -7-oxo-4-thiazide acid 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -7-oxo-6 - ([1, 3] thiazolo [3,2-a] benzimidazol-6-ylmethylene) -4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -6- (7,8-Dihydro-5H-pyran [4,3-d] pyrazolo [5,1-b] [1, 3] oxazol-2-ylmethylene acid) 7 -oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Sodium salt, (5R, 6Z) -7-oxo-6- (5,6,7,8-tetrahydropyrazolo [5,1-b] [1,3] benzoxazol-2-ylmethylene) -4-thia-acid 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid; Y Sodium salt, acid (5R, 6Z) -6-. { [6- (ethoxycarbonyl) -5,6,7,8-tetrahydropyrazoloyl) SJIl.SjoxazoloIS ^ -cjpyridin ^ -ylmethyleneH-oxo ^ -thia-l-azabicyclo [3.2.0] hept-2-ene -2-carboxylic; A method for treating bacterial disease or infection in a patient in need thereof comprising supplying said patient with an effective amount of a compound of formula i as claimed in any one of claims 1 to 19, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. A method according to claim 20 wherein the compound is coadministered with a β-lactam antibiotic. A method according to claim 21 wherein the proportion of the β-lactam antibiotic with the compound is in a range of about 1: 1 to approximately 100: 1. A method according to claim 22 wherein the proportion of the β-lactam antibiotic with the compound is less than 10: 1.